29 results on '"Shaoying Li"'
Search Results
2. High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study
- Author
-
Adam Stephen Zayac, Daniel J. Landsburg, Mitchell E. Hughes, Allison M. Bock, Grzegorz S. Nowakowski, Emily C. Ayers, Mark Ryan Girton, Marie Hu, Amy K. Beckman, Shaoying Li, L. Jeffrey Medeiros, Julie E Chang, Adam Stepanovic, Habibe Kurt, Jose Sandoval-Sus, Mohammad Ali Ansari-Lari, Shalin K. Kothari, Anna Kress, Mina L Xu, Pallawi Torka, Suchitra Sundaram, Stephen D Smith, Kikkeri N Naresh, Yasmin H. Karimi, Narendranath Epperla, David A Bond, Umar Farooq, Mahak Saad, Andrew M Evens, Karan Pandya, Seema G. Naik, Manali Kamdar, Bradley M Haverkos, Reem Karmali, Timothy S Oh, Julie M Vose, Heather R Nutsch, Paul G. Rubinstein, Amina Chaudhry, and Adam J Olszewski
- Subjects
Hematology - Abstract
In this multi-institutional retrospective study, we examined characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS). This rare lymphoma category is defined by high-grade morphologic features, most commonly Burkitt-like, and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements (so-called double-hit). Our results show that HGBL-NOS tumors are heterogeneous: 83% had a germinal center B-cell immunophenotype, 37% a dual expressor immunophenotype (MYC and BCL2 expression), 28% (single-hit) MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage 4 disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included DA-EPOCH-R (43%), R-CHOP (33%), or other intensive chemotherapy programs (11%). We found no significant differences in the rates of complete response (CR, P=0.32), progression-free (PFS, P=0.82), or overall survival (OS, P=0.60) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% (95%CI, 46.9-62.7), and OS was 68.1% (95%CI, 59.7-75.0). In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3x upper limit of normal, and a dual expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS (13% at 2 years). Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R versus R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.
- Published
- 2023
3. High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS): Central Nervous System (CNS) Involvement, Prophylaxis, and Recurrence Risk in a Multi-Institutional Series
- Author
-
Narendranath Epperla, Adam Zayac, Daniel J. Landsburg, Mitchell Hughes, Allison M. Bock, Grzegorz S. Nowakowski, Emily C. Ayers, Mark Girton, Marie Hu, Amy Beckman, Shaoying Li, L. Jeffrey Medeiros, Julie E. Chang, Adam Stepanovic, Habibe Kurt, Jose Sandoval-Sus, M. Ali Ansari-Lari, Shalin K. Kothari, Anna Kress, Mina L Xu, Pallawi Torka, Suchitra Sundaram, Stephen D Smith, Kikkeri N Naresh, Yasmin Karimi, David A. Bond, Umar Farooq, Mahak Saad, Andrew Matthew Evens, Karan Pandya, Seema G Naik, Manali Kamdar, Bradley M. Haverkos, Reem Karmali, Timothy S Oh, Julie M. Vose, Heather Nutsch, Paul Rubinstein, Amina Chaudhry, and Adam J. Olszewski
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
4. Genomic profiles and clinical outcomes of de novo blastoid/pleomorphic MCL are distinct from those of transformed MCL
- Author
-
Ranjit Nair, Luis Fayad, C. Cameron Yin, Pan Tinsu, Yao Yixin, Preetesh Jain, Changying Jiang, David Santos, Jason R. Westin, Sairah Ahmed, Chi Young Ok, Selvi Thirumurthi, L. J. Medeiros, Andy Futreal, Swaminathan Padmanabhan Iyer, Xingzhi Song, Hun Ju Lee, Nathan Fowler, Richard E. Champlin, Wendy Y. Chen, Michael L. Wang, Graciela M. Nogueras González, Shaoying Li, Ruiping Wang, Frederick B. Hagemeister, Jorge E. Romaguera, Krystle Nomie, Omarya Gonzalez-Pagan, Guilin Tang, Guangchun Han, Linghua Wang, Jianhua Zhang, Maria Badillo, Keyur P. Patel, Shaojun Zhang, Holly Hill, Christopher R. Flowers, Guofan Xu, Loretta J. Nastoupil, Onyeka Oriabure, Rashmi Kanagal-Shamanna, and Sattva S. Neelapu
- Subjects
Oncology ,Adult ,Prognostic variable ,medicine.medical_specialty ,Multivariate analysis ,Aneuploidy ,Leukemia, Mast-Cell ,Lymphoma, Mantle-Cell ,Blastoid ,medicine.disease_cause ,Internal medicine ,hemic and lymphatic diseases ,Biopsy ,Medicine ,Humans ,Aged ,Mutation ,Lymphoid Neoplasia ,biology ,medicine.diagnostic_test ,business.industry ,DNA Helicases ,Nuclear Proteins ,Histology ,Hematology ,Genomics ,biology.organism_classification ,medicine.disease ,Prognosis ,SMARCA4 ,business ,Transcription Factors - Abstract
Blastoid and pleomorphic mantle cell lymphomas (MCLs) are variants of aggressive histology MCL (AH-MCL). AH-MCL can arise de novo (AH-DN) or transform from prior classic variant MCL (AH-t). This study is the first integrated analysis of clinical and genomic characteristics of AH-MCL. Patient characteristics were collected from diagnosis (AH-DN) and at transformation (AH-t). Survival after initial diagnosis (AH-DN) and after transformation (AH-t) was calculated. Regression tree analysis was performed to evaluate prognostic variables and in univariate and multivariate analyses for survival. Whole-exome sequencing was performed in evaluable biopsy specimens. We identified 183 patients with AH-MCL (108 were AH-DN, and 75 were AH-t; 152 were blastoid, and 31 were pleomorphic). Median survival was 33 months (48 and 14 months for AH-DN and AH-t, respectively; P = .001). Factors associated with inferior survival were age (≥72 years), AH-t category, Ki-67 ≥50% and poor performance status. AH-t had a significantly higher degree of aneuploidy compared with AH-DN. Transformed MCL patients exhibited KMT2B mutations. AH-MCL patients with Ki-67 ≥50% had exclusive mutations in CCND1, NOTCH1, TP53, SPEN, SMARCA4, RANBP2, KMT2C, NOTCH2, NOTCH3, and NSD2 compared with low Ki-67 (
- Published
- 2020
5. Outcomes of patients with limited-stage aggressive large B-cell lymphoma with high-risk cytogenetics
- Author
-
Kristopher Attwood, Luu Q. Pham, David Peace, Suchitra Sundaram, Sarah Lee, L. Jeffrey Medeiros, Ranjana H. Advani, Brian T. Hess, Daniel J. Landsburg, Adam J. Olszewski, Emma Rabinovich, Stefan K. Barta, Timothy F. Burns, Anshu Giri, Adrienne Groman, Pallawi Torka, Shaoying Li, Joanna C. Zurko, Shalin Kothari, David A. Bond, Madelyn Burkart, Francisco J. Hernandez-Ilizaliturri, Brian T. Hill, Amitkumar Mehta, Emily C. Ayers, Reem Karmali, Jonathon B. Cohen, Julie M. Vose, Michael C. Churnetski, Kami J. Maddocks, Frederick Lansigan, and Yang Liu
- Subjects
Adult ,medicine.medical_specialty ,Vincristine ,Adolescent ,Population ,Gastroenterology ,Cytogenetics ,Young Adult ,Prednisone ,Internal medicine ,Medicine ,Humans ,B-cell lymphoma ,education ,Aged ,Neoplasm Staging ,Aged, 80 and over ,education.field_of_study ,Lymphoid Neoplasia ,business.industry ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Treatment Outcome ,Cohort ,Rituximab ,Lymphoma, Large B-Cell, Diffuse ,business ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
There is a paucity of data regarding outcomes and response to standard therapy in patients with limited-stage (LS) agressive B-cell lymphoma (LS-ABCL) who harbor MYC rearrangement (MYC-R) with or without BCL2 and/or BCL6 rearrangements. We conducted a multicenter retrospective study of MYC-R LS-ABCL patients who received either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or more intensive immunochemotherapy (IIC) plus or minus consolidative involved-field radiation therapy (IFRT). One hundred four patients from 15 academic centers were included. Forty four patients (42%) received R-CHOP, of whom 52% had IFRT. Sixty patients (58%) received IIC, of whom 40% had IFRT. Overall response rate was 91% (84% complete response [CR]; 7% partial response). Patients with double-hit lymphoma (DHL; n = 40) had a lower CR rate compared with patients with MYC-R only (75% vs 98%; P = .003). CR rate was higher in the IFRT vs no-IFRT group (98% vs 72%; P < .001). Median follow-up was 3.2 years; 2-year progression-free survival (PFS) and overal survival (OS) were 78% and 86% for the entire cohort, and 74% and 81% for the DHL patients, respectively. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort and in DHL patients. Our data provide a historical benchmark for MYC-R LS-ABCL and LS-DHL patients and show that outcomes for this population may be better than previously recognized. There was no benefit of using IIC over R-CHOP in patients with MYC-R LS-ABCL and LS-DHL.
- Published
- 2020
6. High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS): Characteristics, Treatment, and Outcomes from 17 Academic US Centers
- Author
-
M. Ali Ansari-Lari, Brad M. Haverkos, Anna Kress, Andrew M. Evens, Yasmin Karimi, Adam J. Olszewski, Julie M. Vose, Adam Zayac, L. Jeffrey Medeiros, David A. Bond, Paul Rubinstein, Emily C. Ayers, Manali Kamdar, Amina Chaudhry, Mitchell E. Hughes, Karan Pandya, Shalin Kothari, Amy Beckman, Suchitra Sundaram, Mina L. Xu, Stephen D. Smith, Marie Hu, Daniel J. Landsburg, Mark Girton, Habibe Kurt, Reem Karmali, Timothy S. Oh, Heather Nutsch, Jose Sandoval-Sus, Seema Naik, Pallawi Torka, Shaoying Li, Narendranath Epperla, and Kikkeri N Naresh
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,High grade B-cell lymphoma ,Not Otherwise Specified ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background: The term HGBL, NOS was introduced by the World Health Organization (WHO) in 2016 for aggressive B-cell lymphomas with Burkitt lymphoma-like (BLL) or blastoid cytomorphology that lack double-hit genetics and do not meet criteria for other entities. Diagnostic patterns and prognosis of these rare tumors are not well understood. We examined the characteristics and outcomes of patients (pts) with HGBL, NOS diagnosed in 17 academic centers across the United States. Methods: We collected retrospective data on HGBL, NOS cases diagnosed by academic hematopathologists in 2017-2021; 8 centers performed a local review by lymphoma pathology experts to confirm fulfillment of the WHO criteria; pathology reports were reviewed centrally. We excluded pts not tested for MYC rearrangement (MYC-R), any double/triple-hit, diffuse large B-cell, or lymphoblastic lymphomas. Immunohistochemistry (IHC) and cytogenetic tests were done locally. Outcomes included rates of complete response (CR), progression-free (PFS) and overall survival (OS) estimated with 95% confidence intervals (CI). Results: Among 126 pts with HGBL, NOS, median age was 64 years (range 18-91), 67% were male, and 3 were HIV+. Advanced stage was present in 68%, poor performance status (PS, ECOG ≥2) in 21%, high serum lactate dehydrogenase (LDH) in 68%, extranodal (EN) sites in 79%, central nervous system (CNS) involvement in 6%, and International Prognostic Index (IPI) ≥ 3 in 55%. Cytomorphology was reported as BLL in 59 (47%) cases, blastoid in 28 (22%), and unspecified in 39 (31%). By IHC, 83% had germinal center B-cell (GCB) phenotype. Using cases with available data, CD10 was expressed in 79%, BCL6 in 81%, MUM1/IRF4 in 48%, MYC in 73%, BCL2 in 55% (dual MYC/BCL2 expressor [DEL]: 37%), CD5 in 13%, and median Ki-67 was 95%. MYC-R (single-hit) was detected in 27% (Fig A), MYC extra copies (EC) in 9%, BCL2-R in 13%, and BCL6-R in 10%. MYC-EC were present in 16% of cases with BCL2-R or BCL6-R, and BCL2/BCL6-EC in 12% of those with MYC-R. Blastoid tumors were more likely than BLL to involve >1 EN site or to have BCL2-R (Fig B). 9 cases were assessed by next generation sequencing and 5 (56%) had a TP53 mutation. Cases which underwent confirmatory pathology review (N=74) did not differ from others clinically but more often had a well-defined HGBL morphology (77% vs 58%, P=.031) and less often MYC-R (20% vs. 37%, P=.004). The most common first-line regimens (among treated pts, N=121) were DA-EPOCH-R (50%) and RCHOP (35%), with few pts receiving HyperCVAD/MA (5%) or CODOX-M±IVAC (2%); 97% received rituximab, and 44% CNS prophylaxis. Pts selected for DA-EPOCH-R vs. RCHOP were younger (median 61 vs. 68 years, P=.006), more often had stage 3/4 (P=.04), BLL morphology (56% vs. 29%, P=.009) or MYC-R (31% vs. 14%, P=.06). CR was attained in 62% of pts, whereas 20% had progressive disease. The most frequent salvage regimens (± rituximab) included ICE (N=12), DHAP (N=6), and GemOx (N=5). 3 pts underwent autologous, and 3 allogeneic transplant (2/3 subsequently relapsed). 13 received chimeric antigen receptor (CAR) T-cells, with response noted in 7 (54%) and CR in 4 (31%); HGBL relapsed in 3/7 (43%) responders. With median follow-up of 2.7 years, 39% of pts relapsed, and 33% died. Of 49 observed relapses, 13 (27%) involved the CNS. PFS estimate at 2 years was 51% (95% CI, 42-60%) and OS was 68% (95% CI, 58-76%; Fig C). PFS and OS were not significantly associated with age or PS, but stage and LDH were prognostic (Fig D-G). Furthermore, PFS did not differ by BLL/blastoid morphology, MYC-R status or DEL status, but non-GCB tumors had somewhat worse PFS (Fig H-J). We observed no significant PFS (or OS) difference between pts selected for RCHOP vs. DA-EPOCH-R (P=.83 for PFS, Fig K; P=.55 for OS) in aggregate or in any subset, except for de novo tumors with BLL morphology (N=41), where DA-EPOCH-R showed a superior 2-year PFS (73% vs 38% for RCHOP, P=.027; stratified by IPI: P=.040, Fig L). Conclusions: HGBL, NOS, as diagnosed in current academic practice, is highly heterogeneous, highlighting the need to classify high-grade lymphomas using molecular rather than morphologic features. Considering poor survival in all age groups (except for few pts with early stage and normal LDH), lack of prognostic significance of MYC-R, DEL status, or cytomorphology, HGBL, NOS needs prospective trials to delineate prognostic biomarkers, the role of intensified chemotherapy, and novel therapeutic approaches. Figure 1 Figure 1. Disclosures Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Hughes: Acerta Pharma: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy; Janssen: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Smith: Acerta Pharma BV: Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; De Novo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Beigene: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Incyte: Consultancy; Incyte Corporation: Research Funding; Karyopharm: Consultancy; KITE pharm: Consultancy; Merck Sharp & Dohme Corp: Research Funding; Ayala (spouse): Research Funding; Bayer: Research Funding; Genentech: Research Funding; Bristol Myers Squibb (spouse): Research Funding; Millenium/Takeda: Consultancy. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bond: Kite/Gilead: Honoraria. Naik: Sanofi: Other: Virtual Advisory Board Member ; Takeda: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Kamdar: ADC Therapeutics: Consultancy; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene (BMS): Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; Genetech: Other; Celgene: Other; SeaGen: Speakers Bureau. Haverkos: Viracta Therapeutics: Consultancy. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding; Roche: Consultancy; Epizyme: Consultancy; Janssen/Pharmacyclics: Consultancy; EUSA: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; AstraZeneca: Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Olszewski: PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; TG Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.
- Published
- 2021
7. Ibrutinib Plus Rituximab and Venetoclax (IRV) Followed By Risk-Stratified Observation or Short Course R-Hypercvad/MTX in Young Patients with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-2 Clinical Trial
- Author
-
Michael Wang, Preetesh Jain, Hun Ju Lee, Chi Young Ok, Holly Hill, Lucy Navsaria, Rashmi Kanagal-Shamanna, Luis Malpica-Castillo, Ranjit Nair, Swaminathan Padmanabhan Iyer, Felipe Samaniego, Wendy Chen, Onyeka Oriabure, Lei Feng, Selvi Thirumurthi, David Santos, Guilin Tang, Francisco Vega, Shaoying Li, Michelle Avellaneda, Maria Badillo, and Christopher R. Flowers
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Background - The WINDOW-1 regimen introduced first-line ibrutinib with rituximab (IR) followed by 4 cycles of R-HCVAD for younger mantle cell lymphoma (MCL) patients (pts) demonstrating 90% CR on IR alone and we aimed to improve the CR rate with the addition of venetoclax. We therefore investigated the efficacy and safety of IR and venetoclax (IRV) followed by risk-stratified observation or short course R-HCVAD/MTX-ARA-C as consolidation in previously untreated young patients with mantle cell lymphoma (MCL). Our aim was to use a triplet chemotherapy-free induction to reduce the toxicity, complications and minimize chemotherapy exposure in MCL pts. Methods - We enrolled 50 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT03710772. Pts received IR induction (Part-1) for initial 4 cycles. Pts were restaged at cycle 4 and received IRV for up to eight cycles (Cycle 5 to Cycle 12) starting with ramp up venetoclax dosing in Cycle 5. All pts who achieved CR prior to cycle 12 continued to receive IRV for 4 cycles (maximum 12 cycles) and then moved to part 2. Pts were stratified into three disease risk groups: high, moderate and low risk categories from the baseline data for assignment to R-HCVAD/MTX-ARA-C as consolidation in part 2 (4 cycles, 2 cycles, or no chemotherapy for high, medium and low risk pts respectively). Briefly, low risk pts were those with Ki-67 ≤30%, largest tumor mass 5 cm or blastoid/pleomorphic histology or if they remain in PR after 12 cycles of part 1. Medium risk are pts which did not belong to low or high-risk category. Those who experienced progression on part 1 went to part 2 and get 4 cycles of part 2. Patient were taken off protocol but not off study, if they remained in PR after 4 cycles of chemotherapy, these patients were followed up for time to next treatment and progression free survival on subsequent therapies. After part 2 consolidation, all pts received 2 years of IRV maintenance. The primary objective was to assess CR rates after IRV induction. Adverse events were coded as per CTCAE version 4. Molecular studies are being performed. Results - Among the 50 pts, the median age was 57 years (range - 35-65). There were 20 pts in high-risk group, 20 pts in intermediate-risk group and 10 pts in low-risk group. High Ki-67 (≥30%) in 18/50 (36%) pts. Eighteen (36%) had high and intermediate risk simplified MIPI scores. Six (12%) pts had aggressive MCL (blastoid/pleomorphic). Among the 24 TP53 evaluable pts, eight pts (33%) had TP53 aberrations (mutated and/or TP53 deletion by FISH). Forty-eight pts received IRV. Best response to IRV was 96% and CR of 92%. After part 2, the best ORR remained unaltered, 96% (92% CR and 4% PR). The median number of cycles of triplet IRV to reach best response was 8 cycles (range 2-12). Fifteen pts (30%) did not receive part 2 chemotherapy, two pts (4%) received 1 cycle, 16 pts (32%) 2 cycles and 13 pts (26%) got 4 cycles of chemotherapy. With a median follow up of 24 months, the median PFS and OS were not reached (2 year 92% and 90% respectively). The median PFS and OS was not reached and not significantly different in pts with high and low Ki-67% or with/without TP53 aberrations or among pts with low, medium or high-risk categories. The median PFS and OS was inferior in blastoid/pleomorphic MCL pts compared to classic MCL pts (p=0.01 and 0.03 respectively). Thirteen pts (26%) came off study - 5 for adverse events, 3 for on study deaths, and 2 for patient choice, 2 patients lost to follow up and one for disease progression. Overall, 5 pts died (3 on trial and 2 pts died off study, one due to progressive disease and another due to COVID pneumonia). Grade 3-4 toxicities on part 1 were 10% myelosuppression and 10% each with fatigue, myalgia and rashes and 3% mucositis. One pt developed grade 3 atrial flutter on part 1. None had grade 3-4 bleeding/bruising. Conclusions - Chemotherapy-free induction with IRV induced durable and deep responses in young MCL pts in the frontline setting. WINDOW-2 approach suggests that pts with low risk MCL do not need chemotherapy but further follow up is warranted. This combined modality treatment approach significantly improves outcomes of young MCL pts across all risk groups. Detailed molecular analyses will be reported. Figure 1 Figure 1. Disclosures Wang: Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Bayer Healthcare: Consultancy; CStone: Consultancy; Celgene: Research Funding; Molecular Templates: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Dava Oncology: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Imedex: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; VelosBio: Consultancy, Research Funding; Mumbai Hematology Group: Honoraria; BGICS: Honoraria; Oncternal: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; The First Afflicted Hospital of Zhejiang University: Honoraria; Lilly: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Juno: Consultancy, Research Funding; BioInvent: Research Funding; Loxo Oncology: Consultancy, Research Funding; Scripps: Honoraria; Physicians Education Resources (PER): Honoraria; OMI: Honoraria; Pharmacyclics: Consultancy, Research Funding; Newbridge Pharmaceuticals: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; Chinese Medical Association: Honoraria; Clinical Care Options: Honoraria; Moffit Cancer Center: Honoraria; Genentech: Consultancy; InnoCare: Consultancy, Research Funding. Jain: Lilly: Consultancy; kite: Consultancy. Iyer: CRISPRX: Research Funding; Seattle Genetics: Research Funding; Rhizen: Research Funding; Merck: Research Funding; Legend: Research Funding; Innate: Research Funding; Spectrum: Research Funding; Trillium: Research Funding; Astra Zeneca: Research Funding; Yingli: Research Funding; Cyclacel: Research Funding. Samaniego: Imbrium: Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding. Vega: CRISPR Therapeutics and Geron: Research Funding; i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding. Flowers: Gilead: Consultancy, Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Cellectis: Research Funding; Bayer: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; Novartis: Research Funding; Genmab: Consultancy; Pfizer: Research Funding; Xencor: Research Funding; TG Therapeutics: Research Funding; 4D: Research Funding; BeiGene: Consultancy; Genentech/Roche: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding; National Cancer Institute: Research Funding; Spectrum: Consultancy; SeaGen: Consultancy; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Epizyme, Inc.: Consultancy; Biopharma: Consultancy; Denovo: Consultancy; AbbVie: Consultancy, Research Funding; Acerta: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Nektar: Research Funding; Morphosys: Research Funding; EMD: Research Funding; Kite: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding.
- Published
- 2021
8. ALK-Negative Anaplastic Large Cell Lymphomas Encompass Distinct Subgroups Including an ALK-Positive-like Subgroup with Favorable Prognosis
- Author
-
Kwok Him Rex Au Yeung, Veronica Russell, William Choi, Alice Wong, Lawrence Tsui, Yu Yan Carmen Lee, Jamilla Li, Harinder Gill, Ho-Wan Ip, Yok Lam Kwong, Tushar Dave, Sarah L. Ondrejka, Govind Bhagat, Amy Chadburn, Sarah C. Rutherford, Jean L. Koff, David L Jaye, Magdalena Czader, Abner Louissaint, Shaoying Li, Jie Xu, C. Cameron Yin, Choon Kiat Ong, Chee Leong Cheng, Amir Behdad, Andrew M. Evens, Peter H. Norgaard, Anne Ortved Gang, Sirpa Leppa, Marja-Liisa Karjalainen-Lindsberg, Jennifer R Chapman, Catalina Amador, Javeed Iqbal, Yuri Fedoriw, Agata M. Bogusz, Andrew G Evans, Ridas Juskevicius, Eric D. Hsi, Kikkeri N Naresh, Sandeep S. Dave, and Eric Tse
- Subjects
hemic and lymphatic diseases ,Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Introduction ALK-negative anaplastic large cell lymphoma (ALK- ALCL) is an uncommon type of T-cell non-Hodgkin lymphoma (T-NHL) with worse prognosis compared to ALK-positive (ALK+) ALCLs. Most published studies on the genomics of T-NHL have focused on peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and previous studies of ALCL described rearrangements in DUSP22 and TP63 and mutations in genes comprising the JAK/STAT pathway as common genetic drivers in ALK- ALCL. The degree to which these drivers affect survival or other molecular features of ALK- ALCL remains unknown. Here, we describe novel subgroups of ALK- ALCL that exhibit distinct survival. One subgroup appears molecularly similar to ALK+ALCLs and is associated with favorable survival while the second subgroup is quite distinct from ALK- ALCLs and associated with poor outcomes. Methods and Results Eighty-two ALK- ALCL patients were recruited to the Atlas of Blood Cancer (ABC) genomes project, a worldwide consortium established to define the molecular origins of blood cancers. Tumor biopsies from these patients, as well as 10 ALK+ ALCL samples for comparison were obtained from participating institutions. Each case was subjected to centralized pathology review by an experienced panel of hematopathologists to ensure the accuracy of the diagnosis. All cases, along with paired normal tissues, were subjected to DNA and RNA (whole exome-level) sequencing on the Illumina platform to identify mutations and expression changes for each of these cases using methods well established in our group and described previously. We first examined the genetic alterations in ALK- ALCLs. In addition to frequently described genetic alterations such as TP63 and DUSP22 rearrangements, as well as mutations in JAK1, STAT3 and TP53, we also detected mutations in ERBB4, SETD2 and KMT2D, which may serve as potential novel drivers and have not been described previously to our knowledge. We next performed comparative gene expression analysis of the ALK- and ALK+ ALCLs. Surprisingly, a proportion of ALK- ALCL cases (38%) clustered together with ALK+ ALCLs and had a signature resembling ALK+ cases, which we designated as "ALK-like ALCL" here. Both the ALK-like ALCLs and the other ALK- ALCL cases showed decreased ALK expression compared to the ALK+ ALCLs by gene expression analysis. These results point to downstream pathways that are common among ALK+ALCLs and ALK-like ALCLs, but different from the other ALK- ALCLs. Gene set enrichment analysis revealed that the ALK-like ALCLs overexpressed genes in pathways related to monocyte and fibroblast activation, whereas the remaining ALK- ALCLs overexpressed genes in the T follicular helper cells, memory T cells and adaptive immune response-related pathways (P Conclusion Our data indicate that ALK- ALCLs represent a heterogeneous group of diseases and comprise at least two distinct subgroups that can be identified based on their similarity to the ALK+ ALCLs. The ALK-like ALCLs demonstrated distinct molecular features and favorable outcomes. Our results provide a potentially new approach to patient risk-stratification and pathological classification of this disease. Disclosures Kwong: Celgene: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Jaye: Stemline Therapeutics: Honoraria. Behdad: Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau; Lilly: Speakers Bureau. Hsi: AbbVie Inc, Eli Lilly: Research Funding. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.
- Published
- 2021
9. The Atlas of Blood Cancer Genomes (ABCG) Project: A Comprehensive Molecular Characterization of Leukemias and Lymphomas
- Author
-
Amy Chadburn, Barbara Xiong, Sarah L. Ondrejka, Govind Bhagat, Eric Tse, Rashmi S. Goswami, Abner Louissaint, Andrew M. Evens, Cassandra Love, Ridas Juskevicius, Sirpa Leppä, Veronica S. Russell, Mina L. Xu, Rachel Kositsky, Choon Kiat Ong, Agata M. Bogusz, Kikkeri N Naresh, Tushar Dave, Shaoying Li, Sandeep S. Dave, Caroline J Roth, Devang Thakkar, Andrew G. Evans, Raju Pillai, Matthew McKinney, Dina Sameh Soliman, Jennifer R. Chapman, Amir Behdad, Jean L. Koff, Adam Snowden, Magdalena Czader, Peter Nørgaard, Yasodha Natkunam, Catalina Amador, Anabel Thurman, Yuri Fedoriw, and Eileen Smith
- Subjects
0303 health sciences ,Atlas (topology) ,Immunology ,Cell Biology ,Hematology ,Computational biology ,Biology ,Biochemistry ,Genome ,3. Good health ,Blood cancer ,03 medical and health sciences ,0302 clinical medicine ,030304 developmental biology ,030215 immunology - Abstract
Introduction Blood cancers are collectively common and strikingly heterogeneous diseases both clinically and molecularly. According to the WHO taxonomy, there are over 100 distinct myeloid and lymphoid neoplasms. Genomic profiling of blood cancers has been applied in a somewhat ad hoc fashion using diverse sequencing approaches including the use of targeted panels, whole exome sequencing, whole genome sequencing, RNA sequencing, etc. The lack of data uniformity has made it difficult to comprehensively understand the clinical and molecular spectrum within and across diseases. Systematic genomic approaches can address the central challenges in the diagnosis and treatment of blood cancers. For the diagnosis of blood cancers, the incorporation of genomics could greatly enhance the accuracy and speed of clinical diagnostics. Genomics could also inform their pathology classification. However, these applications must be preceded by a clear understanding of the particular genetic aberrations and expression profiles that unite and distinguish different leukemias and lymphomas. Therapeutic development can also be aided by genomic approaches through identification of new targets and establishing the relevance of existing targets and treatments. Targeted therapies including those directed at specific surface markers (e.g. CD19, CD30 and CD123) or molecular targets (e.g. BCR-ABL fusions, IDH1 mutations and EZH2 mutations) are rarely restricted to a single disease, with most occurring in multiple blood cancers. A systematic understanding of the presence or overlap of these targets within or across blood cancers would significantly expand the therapeutic possibilities and better enable the use of existing therapies in both common and rare cancers. However, such therapeutic possibilities need to be established through a rigorous, data-driven approach. We initiated the Atlas of Blood Cancers Genomes (ABCG) project to systematically elucidate the molecular basis of all leukemias and lymphomas by building upon advances in genomic technologies, our capabilities for data analysis and economies of scale. Using a uniform approach to systematically profile all blood cancers through DNA and RNA sequencing at the whole exome/whole transcriptome level, we aim to link genomic events with clinical outcomes, disease categories and subcategories, thereby providing a complete molecular blueprint of blood cancers. Methods/Results The ABCG project consists of collaborators from 25 institutions around the world who have collectively contributed samples from 10,481 patients comprising every type of blood cancer in the current WHO classification. The samples include thousands of myeloid leukemias and mature B cell lymphomas, hundreds of Hodgkin lymphoma and plasma cell myeloma, as well as every rare type of hematologic malignancy (along with case-matched normal tissue). All cases were de-identified and their associated pathology and detailed clinical information entered into a purpose-built web-based system that included disease-specific data templates. All cases were subjected to centralized pathology review and clinical data review by experienced hematopathologists and oncologists. All 10,481cases are being sequenced at the DNA and RNA level, and are being profiled to define the genetic alterations and expression changes that are characteristic of each disease. Analysis will include translocations, copy number alterations, and viral status. These molecular features will be examined in conjunction with genetic events, pathologic factors, and the clinical features. We have already generated results for ALK-negative anaplastic large B cell lymphoma and primary mediastinal B cell lymphomas (N=210). These data demonstrate novel subgroup and molecular discoveries that are enabled by integrative DNA and RNA sequencing analysis and the examination of molecular features across different diseases as well as within individual entities. In addition, other disease entities and the collective data will be presented in the meeting. Conclusion The ABCG project will comprehensively study the genetic and clinicopathological features of all blood cancers using systematic genomic approaches. We anticipate our data, approaches and results will serve as a lasting resource for the molecular classification and therapeutic development for leukemias and lymphomas. Disclosures McKinney: Novartis: Research Funding; Nordic Nanovector: Research Funding; Molecular Templates: Consultancy, Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Incyte: Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy; Celgene: Consultancy, Research Funding; BTG: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Verastem: Consultancy. Behdad: Lilly: Speakers Bureau; Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau.
- Published
- 2021
10. Immune-Depleted Tumor Microenvironment Signature Is Associated with BTK Inhibitor Resistance in Mantle Cell Lymphoma
- Author
-
Yuxuan Che, Yijing Li, Felix Frenkel, Nathan Fowler, Francisco Vega, Alexander Bagaev, Nikita Kotlov, Holly Hill, Chi Young Ok, Viktor Svekolkin, Ravshan Attaulakhanov, Preetesh Jain, Rashmi Kanagal-Shamanna, Evgeniy Egorov, Krystle Nomie, Yixin Yao, Michael Wang, Vitaly Segodin, Lucy Navsaria, Shaoying Li, and Christopher R. Flowers
- Subjects
Tumor microenvironment ,biology ,Chemistry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Immune system ,biology.protein ,Cancer research ,medicine ,Bruton's tyrosine kinase ,Mantle cell lymphoma - Abstract
Background - The tumor microenvironment (TME) plays a vital role in the growth and survival of mantle cell lymphoma (MCL) cells. However, characterization of the TME transcriptomic profile in MCL, its prognostic impact and response to Bruton's tyrosine kinase inhibitors (BTKi) is unknown. Unlike other lymphomas, the TME in MCL patients has not been fully characterized at the transcriptomic and genomic levels. To further understand the relevance of tumor-immune landscape in tissue microenvironments in the context of BTKi, we performed multi-omic profiling of the TME in tissues from MCL patients. Methods - Tissue biopsies were collected from MCL patients treated with BTKi. The study was conducted under an Institutional Review Board-approved protocol at The University of Texas MD Anderson Cancer Center. A total of 42 patients treated with BTKi were included. Among evaluable patients, DNA and RNA extraction was performed from fresh biopsies from lymph nodes and non-nodal tissues (including bone marrow). Whole exome (WES) and bulk RNA sequencing (RNA-seq) were performed to assess the somatic mutation profile, copy number abnormalities and gene expression profile to identify TME gene clusters. RNA sequencing data from an independent cohort of MCL patients from Scott et al (n = 122) was analyzed. Joint WES and RNA-seq, mutation calling, expression analysis, and cell type deconvolution from the transcriptome were performed using the BostonGene automated pipeline. Overall survival was calculated after starting BTKi therapy. Results - We obtained 42 MCL tissue samples (28 lymph nodes, 13 various tissues and one bone marrow) from patients treated with BTKi. Samples were obtained at/after starting treatment with BTKi at clinical progression. Unsupervised clustering based on the activities of the proposed transcriptomic signatures identified four distinct MCL subtypes based on tumor-immune cell gene signatures. We identified the four distinct MCL microenvironment signatures - normal lymph node like (N; n = 27), immune cell-enriched or "Hot" (IE; n = 46), mesenchymal (M; n = 44) and immune depleted/deserted or 'cold' (D; n = 51). The tumor proliferation rate signature and PI3K pathways were significantly overexpressed in immune-depleted (D) TME group. Evaluable patients were further classified based on response to BTKi as sensitive (n = 17), primary resistant (n = 11) or acquired resistant (n = 11). The TME was further dichotomized into immune cell rich and immune desert categories based on commonly involved immune cells and pathways. BTKi resistant MCL primarily exhibited immune depleted TME subtype. To explore the somatic mutation profile in relation to TME clusters, we performed a multiomic analysis combining WES data with RNA sequencing data and depicted according to the four TME clusters. Somatic mutations in TP53, NSD2, NOTCH1, KMT2D, SMARCA4, which were previously reported in ibrutinib-resistant MCL and/or in refractory high-risk MCL patients, were predominant in the immune-depleted TME cluster (D). Conclusions - Overall, we defined BTKi sensitivity and resistance by immune-hot and immune-cold TME portraits, respectively. The immune-depleted TME subtype (D) was characterized by dominant proliferation gene signature, overexpressed PI3K pathway, BTKi resistance and poor outcomes in MCL patients. Disclosures Jain: Lilly: Consultancy; kite: Consultancy. Nomie: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Segodin: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Egorov: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Vega: CRISPR Therapeutics and Geron: Research Funding; i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding. Svekolkin: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Bagaev: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Frenkel: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Attaulakhanov: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flowers: Sanofi: Research Funding; Amgen: Research Funding; EMD: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; Pfizer: Research Funding; Celgene: Consultancy, Research Funding; Denovo: Consultancy; Novartis: Research Funding; Nektar: Research Funding; Epizyme, Inc.: Consultancy; Morphosys: Research Funding; Genmab: Consultancy; AbbVie: Consultancy, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Biopharma: Consultancy; Pharmacyclics/Janssen: Consultancy; Kite: Research Funding; Guardant: Research Funding; SeaGen: Consultancy; Cellectis: Research Funding; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Allogene: Research Funding; Adaptimmune: Research Funding; Spectrum: Consultancy; Acerta: Research Funding; 4D: Research Funding; Pharmacyclics: Research Funding. Wang: BGICS: Honoraria; Newbridge Pharmaceuticals: Honoraria; BioInvent: Research Funding; VelosBio: Consultancy, Research Funding; Juno: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Hebei Cancer Prevention Federation: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Mumbai Hematology Group: Honoraria; Scripps: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Loxo Oncology: Consultancy, Research Funding; Moffit Cancer Center: Honoraria; Lilly: Research Funding; Bayer Healthcare: Consultancy; OMI: Honoraria; Imedex: Honoraria; Epizyme: Consultancy, Honoraria; Celgene: Research Funding; Physicians Education Resources (PER): Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Chinese Medical Association: Honoraria; Clinical Care Options: Honoraria; Dava Oncology: Honoraria; CStone: Consultancy; DTRM Biopharma (Cayman) Limited: Consultancy; Genentech: Consultancy; Oncternal: Consultancy, Research Funding; Molecular Templates: Research Funding; CAHON: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding.
- Published
- 2021
11. Comprehensive Analysis of Factors Predictive for Time to Transformation and Risk of Transformation in Patients (pts) with Mantle Cell Lymphoma
- Author
-
Preetesh Jain, Dayoung Jung, Lucy Navsaria, Chi Young Ok, Ranjit Nair, Christopher R. Flowers, Pan Tinsu, Keyur P. Patel, Selvi Thirumurthi, Francisco Vega, Shaoying Li, Raphael E Steiner, Sairah Ahmed, Rashmi Kanagal-Shamanna, Guilin Tang, Graciela M. Nogueras González, Michael Wang, Guofang Xu, Holly Hill, and Hun Ju Lee
- Subjects
medicine.medical_specialty ,Univariate analysis ,Framingham Risk Score ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Continuous variable ,chemistry.chemical_compound ,chemistry ,Median follow-up ,Internal medicine ,Ibrutinib ,Cohort ,medicine ,In patient ,Mantle cell lymphoma ,business - Abstract
Introduction: Mantle cell lymphoma commonly presents as classic variant histology, however 10-30% patients (pts) can transform into an aggressive histology (blastoid and/or pleomorphic variants). We have previously reported that genomic profile and clinical outcomes of transformed MCL pts are distinct from classic variant pts who never transformed (CNT) and that transformed pts have poor clinical outcomes. In this study, we analyzed the factors at initial diagnosis which can predict the time to transformation and the risk for transformation in a cohort of 369 pts with MCL. Methods: We analyzed charts from 369 pts with MCL (293 were CNT and 76 were transformed MCL). Statistical analysis was performed from baseline pt characteristics collected from the time of initial diagnosis in CNT group and at the time of initial diagnosis of classic variant MCL who later transformed (t-MCL). Time to transformation (TTT) was calculated from initial diagnosis to the date of transformation in those who transformed and last follow up in those who never transformed. Univariate and multivariate (MVA) logistic regression modeled the risk of transformation. Classification and regression tree (CART) analysis was performed to identify optimal cut off in categorical variables predictive of TTT. Results: Among the 369 pts, the median age was 62 yrs (range 34-90). Ki-67% values were available in 133 pts (36% of total) and median Ki-67% was 25% (range 1-80). Three hundred eight pts (84%) had initial bone marrow involvement and 66 pts (18%) had leukemic phase at diagnosis. The median follow up was 133 months and the median overall survival (OS) was 95 months and 43% were alive at the time of this analysis. Discernible difference were noted in pts who belong to t-MCL group compared to pts in the CNT group, pts in t-MCL group exhibited - higher values of median Ki-67% (30% vs 20% in CNT; p=0.04), higher LDH levels, higher proportions of pts with high risk simplified MIPI risk score, leukemic phase at initial diagnosis, complex karyotype and lower hemoglobin. First line treatments received by both groups were similar. Eleven pts got anti-CD19 CART therapy at some point and 7 pts were t-MCL and 4 were CNT group. The median time to transformation in months for those who transformed was 39 (range 5-240 months) while in CNT it was 51 months (1-257 months). We further identified that incremental Ki-67% was significantly associated with TTT and OS (Figure-1A-B). Using CART analysis we identified Ki-67% ≥60 is significantly associated with shorter TTT (HR, 6.26; 95% CI 2.58-15.21; p 729 IU/L), higher platelet count > 180 and high absolute lymphocyte count > 5000 k/ul were predictive of shorter TTT. Logistic regression model showed factors associated with the risk of transformation. In univariate analysis, higher risk was significantly associated with Ki-67% as a continuous variable - OR 1.03 (95% CI 1.01-1.05; p=0.006), leukemic phase at diagnosis, high risk MIPI score and complex cytogenetics. First line treatment with ibrutinib compared to R-HCVAD, was associated with decreased risk of transformation. In MVA, ibrutinib/BTK inhibitor therapy (n=51) as first line therapy was associated with decreased risk of transformation while CNS involvement was associated with higher risk of transformation. Conclusions: Routinely available clinical variables can help determine the risk for transformation of MCL and time to transformation. Progressive increase in Ki-67 and high MIPI risk score is associated with shorter TTT and increases the risk for transformation. Earlier usage of BTK inhibitor therapy may reduce the risk of developing histologic transformation in MCL pts. Disclosures Lee: Seattle Genetics: Research Funding; Takeda: Research Funding; Aptitude Health: Speakers Bureau; Oncternal Therapeutics: Research Funding; Guidepoint Blogal: Consultancy; Celgene: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Vega:NCI: Research Funding. Flowers:Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; OptumRx: Consultancy; TG Therapeutics: Research Funding; BeiGene: Consultancy; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Kite: Research Funding; Bayer: Consultancy. Wang:Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Dava Oncology: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; InnoCare: Consultancy; Nobel Insights: Consultancy; OncLive: Honoraria; Loxo Oncology: Consultancy, Research Funding; MoreHealth: Consultancy; Oncternal: Consultancy, Research Funding; Targeted Oncology: Honoraria; Acerta Pharma: Research Funding; Guidepoint Global: Consultancy; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Lu Daopei Medical Group: Honoraria; Juno: Consultancy, Research Funding; VelosBio: Research Funding; BioInvent: Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding.
- Published
- 2020
12. Complex Karyotype Is a Significant Predictor for Worst Outcomes in Patients with Mantle Cell Lymphoma (MCL) Treated with BTK Inhibitors - Comprehensive Analysis of 396 Patients
- Author
-
Sairah Ahmed, Chi Young Ok, Graciela M. Nogueras González, Francisco Vega, Preetesh Jain, Guilin Tang, Yijing Li, Loretta J. Nastoupil, Shaoying Li, C. Cameron Yin, Yang Liu, Yuxuan Che, Ranjit Nair, Wendy Chen, Maria Badillo, Christopher R. Flowers, Jason R. Westin, Lucy Navsaria, Selvi Thirumurthi, Onyeka Oriabure, Rashmi Kanagal-Shamanna, and Michael Wang
- Subjects
Response rate (survey) ,medicine.medical_specialty ,Treatment response ,Btk inhibitors ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Median follow-up ,Internal medicine ,Medicine ,In patient ,Mantle cell lymphoma ,Poor performance status ,Progression-free survival ,business - Abstract
Introduction: Complex karyotype (Cx) refers to ≥3 unrelated cytogenetic abnormalities in addition to t(11;14) in MCL patients (pts). In limited pts treated with chemotherapy, pts with Cx exhibited poor outcomes compared to non-Cx group. Prognostic impact of Cx in pts treated with BTKi is unclear. We present the largest and most comprehensive analysis on the prognostic impact of Cx in MCL pts. Methods: We analyzed charts from 396 MCL pts with karyotype data. (271 were non-Cx and 125 were Cx). Karyotype status at initial MCL diagnosis was denovo (DN) while previously treated pts were secondary (S). Among Cx, n=80 pts were DN-Cx and 45 were S-Cx while in non-Cx group, 224 were DN-non-Cx and S-non-Cx were 47 pts. TP53 mutation/FISH data was available (n=134; 46 positive, 88 negative). Pt characteristics were obtained from the time of karyotype testing (at initial diagnosis in DN and at the time of testing in S group). Overall survival (OS) was calculated from test date to the last follow up and progression free survival (PFS) after first line therapy from treatment date to date of progression/death. Univariate and multivariate logistic regression modeled the risk of event and treatment response. Results: Cx pts had significant differences compared to non-Cx, including median Ki-67 (40 vs 20%), sMIPI (median 6 vs 4), poor performance status (p.s.), CNS involvement (7 vs 2%), blastoid (22 vs 7%), pleomorphic (12 vs 3%), higher LDH, WBC, ALC and β2M levels and low Hb and platelet counts, prior BTKi (35 vs 15%), TP53 positive (75 vs 17%), shorter median follow up from the test date (18 vs 33 months). Overall, 70 (56%) in Cx and 70 (26%) in non-Cx had died. Univariate analysis for OS showed, advanced age, higher values of Ki-67, WBC, LDH, β2M, MIPI scores, number of chromosomal aberrations, B symptoms, splenomegaly, CNS involvement, poor p.s., prior BTKi, blastoid/pleomorphic histology, TP53 positive status, non-responder to first line therapy and Cx (median 35 months vs 101 months in non-Cx respectively; p In addition to other factors, Cx was associated with shorter PFS in univariate (median 12 vs 48 months for non-Cx; p Among the 107 pts with Cx and 221 with non-Cx with available treatment data, 31 in Cx (1-C) and 101 in non-Cx were treated with BTKi with/without chemo-immunotherapy. Median PFS in both Cx and non-Cx groups was significantly longer with BTKi based therapies compared to R-HCVAD, R-Chemo and other therapies (excluding CAR-T and 1 pt with venetoclax-BTKi). PFS in S-Cx category (n=36), the worst category for survival outcomes, was not influenced by BTKi but was improved with CAR-T therapy (1-D). BTKi therapy improved PFS and OS in Cx and DN-Cx categories compared to R-HCVAD, R-chemo, other therapies (with/without SCT) but did not impact on S-Cx category with the worst outcomes. Response rate to BTKi were (92% vs 74%; p=0.01) in pts with non-Cx and Cx respectively. Conclusions: Cx pts remain a high risk MCL cohort in the BTKi era. Within Cx pts, DN-Cx had better outcomes compared to S-Cx category with the worst outcomes. Outcomes and treatment responses in non-Cx were significantly superior compared to Cx pts. CAR-T therapy holds a great promise for improving outcomes in S-Cx karyotype MCL patients. Disclosures Westin: BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy. Nastoupil:Bayer: Honoraria; Gamida Cell: Honoraria; Gilead/KITE: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Genentech, Inc.: Honoraria, Research Funding; LAM Therapeutics: Research Funding; TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding. Vega:NCI: Research Funding. Flowers:Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Cancer Prevention and Research Institute of Texas: Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees. Wang:Acerta Pharma: Research Funding; Juno: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; Lu Daopei Medical Group: Honoraria; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; InnoCare: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; VelosBio: Research Funding; Verastem: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Nobel Insights: Consultancy; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Molecular Templates: Research Funding.
- Published
- 2020
13. Immune Evasion Phenotype Is Common in Richter Transformation Diffuse Large B-Cell Lymphoma and Correlates with CD30 Expression
- Author
-
Shaoying Li, Siba El Elhussein, Joseph D. Khoury, L. Jeffrey Medeiros, Stephen K. Gruschkus, Sanam Loghavi, Hong Yang, Keyur P. Patel, Beenu Thakral, Peng Wei, Rashmi Kanagal-Shamanna, Ellen J. Schlette, Warren Fiskus, Kapil N. Bhalla, Jie Xu, Zhenya Tang, Kirill A. Lyapichev, William G. Wierda, and Nitin Jain
- Subjects
CD30 ,Richter transformation ,Immunology ,Cell Biology ,Hematology ,Biology ,Evasion (ethics) ,medicine.disease ,Biochemistry ,Phenotype ,Immune system ,Cancer research ,medicine ,Diffuse large B-cell lymphoma - Abstract
BACKGROUND Richter transformation (RT), most commonly manifesting as diffuse large B-cell lymphoma (RT-DLBCL), occurs in 2-8% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients who develop RT-DLBCL have a median overall survival (OS) of less than 12 months despite intensive chemoimmunotherapy. Immune checkpoint inhibitors (PD1 inhibitors) have shown clinical activity in RT-DLBCL, thus providing for a novel therapeutic approach. Such studies have shown a response to PD1 blockade associated with an immune evasion phenotype based on PD1 and/or PD-L1 expression on tumor cells, but the status of predictive biomarkers of response to PD1 blockade in RT-DLBCL remains largely unknown. Other lymphomas associated with PD-L1 expression often express CD30 and harbor Epstein-Barr virus (EBV), both presenting additional possible therapeutic targets, but few studies have assessed the frequency of these markers in RT-DLBCL. METHODS The study group consists of 64 patients with extramedullary biopsy confirmed RT-DLBCL. Expression of PD1, PD-L1, CD30, and microsatellite instability (MSI) status (hMLH1, hMSH2, hMSH6, PMS1) was assessed using immunohistochemistry on formalin-fixed paraffin-embedded pre-treatment tumor samples. EBV-encoded RNA was evaluated using colorimetric in situ hybridization. PD1 and PD-L1 expression levels were categorized on the basis of tumor cell expression as follows: negative (50%). An "immune evasion phenotype" (IEP) was defined as RT-DLBCL cases having high-positive expression of PD1 and/or PD-L1 on tumor cells. The level of PD1-positive tumor-infiltrating lymphocytes (TILs) was estimated as a fraction of total lymphocytes and categorized as negative/low vs. brisk (>20%). Demographic and clinical features by IEP status were compared using chi-square/Fisher's exact tests for categorical variables and t-tests/Wilcoxon rank-sum tests for continuous variables. Kaplan-Meier analysis and corresponding log-rank tests were used to estimate and compare OS between groups defined by clinical features. RESULTS Patients included 41 men (64.1%) and 23 women with a median age of 66.2 years (range, 45.3-84.9 years). The interval from initial CLL/SLL diagnosis to RT-DLBCL was 4.8 years. PD-L1 expression on tumor cells was high-positive in 13 (20.3%), low-positive in 10 (15.6%), and negative in 41 (64.1%) cases. PD1 expression on tumor cells was high-positive in 19 (30.2%), low-positive in 4 (6.3%), and negative in 40 (63.5%) cases. Accordingly, 28/64 (43.7%) patients had IEP+ RT-DLBCL. A brisk level of PD1+ TILs was significantly more common in IEP1+ compared with IEP- tumors (17/28, 60.7% vs. 5/34, 14.7%; p=0.001). In addition, CD30 expression was significantly more common in IEP+ compared with IEP- RT-DLBCL (14/20, 70% vs. 1/27, 3.7%; p=0.0320). Two (2/36; 5.5%) cases were positive for EBV, both IEP+. There was no significant difference between the two groups in terms of age, sex, or time to transformation. Assessment of mismatch repair proteins demonstrated an MSI-stable phenotype in all but one (1/18; 5.5%) case; this case was MSI-high, IEP-, and had a brisk infiltrate of PD1+ TILs. Patients had a median OS of 13.6 months (95% CI: 10.0-19.5 months). Notably, patients with brisk PD1+ TILs had a significantly better OS compared to those with a negative/low infiltrate (p=0.0285). CONCLUSIONS We demonstrate that IEP+ status is common in RT-DLBCL and correlates with CD30 expression and a brisk infiltrate of PD1+ TILs. Our data also suggest that IEP+ status correlates with more favorable OS in RT-DLBCL. Disclosures Jain: Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding.
- Published
- 2020
14. Outcomes of Acalabrutinib Failures in Relapsed Mantle Cell Lymphoma
- Author
-
Linghua Wang, Yuxuan Che, Shaojun Zhang, Wendy Chen, Chi Young Ok, Francisco Vega, Sairah Ahmed, Preetesh Jain, Maria Badillo, Ranjit Nair, Onyeka Oriabure, Rashmi Kanagal-Shamanna, Guilin Tang, Christopher R. Flowers, Jason R. Westin, Michael Wang, Lucy Navsaria, Shaoying Li, Loretta J. Nastoupil, C. Cameron Yin, Omar Moghrabi, Hun Ju Lee, and Felipe Samaniego
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Disease progression ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Discontinuation ,chemistry.chemical_compound ,chemistry ,Median follow-up ,Ibrutinib ,Internal medicine ,Medicine ,Acalabrutinib ,Mantle cell lymphoma ,Lost to follow-up ,business ,health care economics and organizations ,Lenalidomide ,medicine.drug - Abstract
Introduction: Acalabrutinib is an irreversible BTK inhibitor (BTKi) in the treatment of relapsed patients (pts) with mantle cell lymphoma (MCL). We and others have previously reported that ibrutinib resistant MCL have poor outcomes and BTK mutations are uncommon in ibrutinib resistant MCL. However, the outcomes, causes of discontinuation, management and mutational landscape in MCL pts who discontinued acalabrutinib are not described. Methods: We reviewed charts from all relapsed MCL pts treated with acalabrutinib (n=26) in the relapsed setting and identified 21 pts who discontinued acalabrutinib, described in this analysis. Outcomes and management of patients after discontinuing acalabrutinib are reported. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed in 9 pts who progressed on acalabrutinib (10 tumor specimens and 5 matched germline samples); among these pts, 4 tumors were collected before acalabrutinib and 6 were collected after progression on acalabrutinib. One patient had paired sample at both time points (baseline and progression). Results: Among the 21 pts who discontinued acalabrutinib, 15 (71%) discontinued due to disease progression (2 pts transformed from classic to pleomorphic MCL at progression) and 6 discontinued due to intolerance (one for fatigue and idiopathic encephalopathy, one due to unrelated severe aortic stenosis, 2 others due to therapy related myelodysplasia and 2 due to cardiac issues). Two pts with cardiac issues had pre-existing coronary artery disease and one of them developed new onset atrial fibrillation. Overall, the median number of prior treatments was 2 (range, 1-3); all had prior chemo-immunotherapy and none with ibrutinib. The median duration on treatment with acalabrutinib was 8.3 months (1 to 50 months) and the median number of cycles of acalabrutinib treatment was 8 (range, 1-53). Thirteen pts had complete remission (CR) as their best response on acalabrutinib, 5 were primary refractory and 3 achieved partial remission. At the time of starting acalabrutinib, 12 pts had classic and 9 pts had blastoid (n=6) or pleomorphic (n=3) features, the median Ki-67 expression was 50% (range, 10-100). Pts who progressed, received acalabrutinib for a median duration of 8.3 months (range, 1-50) while those with intolerance, received acalabrutinib for a median duration of 9.4 months (range, 4-31). Median follow up after discontinuation was 38 months and the median post acalabrutinib survival was 24 months (not reached for progression and 7.4 months for intolerance; p =0.02, Figure-1A-B). Patients who discontinued due to intolerance could not get subsequent treatment for MCL. Among the 15 pts who progressed on acalabrutinib, 14 pts received systemic therapies for MCL [eight received ibrutinib based therapies (4 non responders, 3 achieved CR and 1 were PR and all pts progressed subsequently), 5 got chemo-immunotherapy, bortezomib, lenalidomide and progressed and one pt did not receive any treatment and was lost to follow up and died. Among the 15 pts who progressed on acalabrutinib, 6 patients who received anti-CD19 CAR-T therapy had significantly longer survival compared to those who did not get CART therapy; p = 0.007, Figure-1C. For all pts, at the time of last follow up, 10 pts were alive and in remission under follow up while 11 were dead. Recurrently mutated genes in these tumors included ATM (6/10; 60%), TP53 (4/10; 40%), KMT2C (3/10), MYCN (2/10), NOTCH1 (2/10), NOTCH3 (2/10), and MEF2B (2/10) (1-D). We did not detect any mutation or copy number alterations in BTK, PLCG2, TRAF2/3 and MYD88 that have been reported previously to be associated with ibrutinib resistance. To investigate the mutation evolution on acalabrutinib treatment, mutation profiles, particularly the mutation variant allelic fractions (VAFs), were compared between the baseline and progression samples from one patient. Mutation of MYCN, MEF2B, ATM, and NOTCH1 were identified in both tumors at similar VAFs, whereas mutation of CARD11 (two mutations), NLRC5 and B2M were detected only at progression. Conclusions: Relapsed MCL pts who fail acalabrutinib have poor outcomes. Advent of CART therapy has significantly improved survival of these heavily refractory pts. In this small cohort, we did not observe BTK mutations associated with acalabrutinib resistance in MCL pts. Further studies are ongoing to determine acalabrutinib resistance mechanism in MCL. Disclosures Lee: Takeda: Research Funding; Aptitude Health: Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Research Funding; Oncternal Therapeutics: Research Funding; Guidepoint Blogal: Consultancy; Celgene: Research Funding. Westin:Astra Zeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy; Kite: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; 47: Research Funding. Nastoupil:LAM Therapeutics: Research Funding; TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Gilead/KITE: Honoraria; Gamida Cell: Honoraria; Bayer: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Vega:NCI: Research Funding. Flowers:Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Celgene: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Bayer: Consultancy; Eastern Cooperative Oncology Group: Research Funding; AbbVie: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Kite: Research Funding; Spectrum: Consultancy; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Burroughs Wellcome Fund: Research Funding; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; BeiGene: Consultancy; Acerta: Research Funding. Wang:AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Nobel Insights: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; VelosBio: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Oncternal: Consultancy, Research Funding; Molecular Templates: Research Funding; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Dava Oncology: Honoraria; Verastem: Research Funding; Guidepoint Global: Consultancy; Lu Daopei Medical Group: Honoraria; InnoCare: Consultancy; Acerta Pharma: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses.
- Published
- 2020
15. Whole Exome and Transcriptome Sequencing in 1042 Cases Reveals Distinct Clinically Relevant Genetic Subgroups of Follicular Lymphoma
- Author
-
William W.L. Choi, Ilja Nystrand, Tushar Dave, David L. Jaye, Sarah L. Ondrejka, Anupama Reddy, Eric Powers, Jie Xu, Cathy Burton, Sirpa Leppä, Matthew McKinney, Xiang Li, Rashmi S. Goswami, Anne Ortved Gang, Alexandra E. Kovach, Lin Wang, Raju Pillai, Rex Au-Yeung, C. Cameron Yin, Yuri Fedoriw, Michael C. Churnetski, Shaoying Li, Razvan Panea, Govind Bhagat, Cassandra Love, Ridas Juskevicius, Eric D. Hsi, Jason Yongsheng Chan, Nathan D. Montgomery, Panu E. Kovanen, Amir Behdad, Chad M. McCall, Abner Louissaint, Mary Ann Thompson Arildsen, Chee Leong Cheng, Amy Chadburn, Daryl Ming Zhe Cheah, Catalina Amador, Jan Delabie, Rebecca J. Leeman-Neill, Shin Yeu Ong, Dina Sameh Soliman, Emily F Mason, Barbara Xiong, Agata M. Bogusz, Felik Paulua, Christopher R. Flowers, John Goodlad, Jean L. Koff, Eric Tse, Jennifer R. Chapman, Mette Ølgod Pedersen, Johannes Dunkel, Richard Burack, Kikkeri N. Naresh, Magdalena Czader, Peter Nørgaard, Nishitha Reddy, Vincent Sarno, Andrew G. Evans, Annika Pasanen, Lianne Lee, Eileen Smith, Amber Landis, Sarah Wildeman, Ji Yuan, Rachel Kositsky, Qiu Qin, Jadee L. Neff, Sandeep S. Dave, Neta Goldschmidt, Marja-Liisa Karjalainen-Lindsberg, Hina Naushad Qureishi, Andrea Stafford Hintz, and Rafael Lopez
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Immunology ,Follicular lymphoma ,Copy number analysis ,Merkel cell polyomavirus ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Copy-number variation ,Exome ,health care economics and organizations ,biology ,Genetic heterogeneity ,business.industry ,Cell Biology ,Hematology ,biology.organism_classification ,BCL6 ,medicine.disease ,3. Good health ,030104 developmental biology ,Family medicine ,business ,Diffuse large B-cell lymphoma ,030215 immunology - Abstract
Follicular Lymphoma (FL) is the most common indolent lymphoma derived from light zone germinal center B cells and characterized by a t(14;18) translocation resulting in upregulation of BCL2 in over 80% of cases. This translocation alone is not sufficient for tumorogenesis, and must be combined with additional genetic mutations to transform B cells. FL is incurable and the disease course can be highly varied, with survival ranging from a few months to decades following diagnosis and treatment with standard chemoimmunotherapy. The heterogeneity of FL poses major challenges to identifying the association of genetic alterations and clinical outcome. Current WHO guidelines recommend establishing grade for each FL case with grade 3 thought to be more aggressive than 1 and 2. The genetic basis and clinical implications of grade in FL are unclear. Recent sequencing studies have identified many genes found to be recurrently mutated in FL including KMT2D and CREBBP. However, the degree to which genetic alterations cooperate with each other or contribute to clinical outcome is unclear. Based on the observed mutational rates in follicular lymphoma, we estimated 900 cases were needed to comprehensively delineate the genetic alterations that underlie histologic grade and clinical outcome. Accordingly, we enrolled a cohort of 1042 patients with newly diagnosed FL. All treated patients received rituximab-containing standard regimens. To go beyond the identification of gene-coding events, we developed a very large panel of 110 Mbp covering exonic (~40Mbp) and non-exonic regions (~70Mbp) of interest to enable a wide range of genomic analysis including mutation calling in both coding and non-coding regions, rearrangement detection, viral identification, and copy number analysis. In addition to the whole exome, we extended coverage to include introns, promoters, and untranslated regions of all known driver genes in cancer. We included the entirety of the immunoglobulin loci, T-cell receptor loci and CD3 loci to detect clonotypes and rearrangements. We also included lymphoma-relevant long non-coding RNAs, microRNAs, enhancers, and breakpoint-prone regions. For viral detection, we targeted the genomes of eight cancer-related viruses: Epstein-Barr virus, human papillomavirus, human immunodeficiency virus, hepatitis B, hepatitis C, Kaposi's sarcoma-associated herpesvirus, human T-lymphotropic virus, and Merkel cell polyomavirus. In addition, to enable high resolution identification of copy number variation (CNV) calls, the entire genome was tiled with probes spaced 10kb apart. DNA and RNA were extracted from all tumors and their paired normal samples, prepared into DNA and RNA sequencing libraries and subjected to sequencing on the Illumina platform to a targeted coverage of 150X. Somatic events were identified and further filtered to identify driver events in both coding and non-coding regions. FLs demonstrated a significant degree of genetic heterogeneity with over 100 genes mutated with a frequency of at least 2%. Nearly 100% of FL cases had a mutation in at least one chromatin-modifying gene. The most frequently mutated genes in follicular lymphoma were KMT2D, BCL2, IGLL5 and CREBBP. In addition, we identified frequent mutations in SPEN, BIRC6 and SETD2. To our knowledge, this is the first description of alterations in these genes in FL. Transcriptome analysis indicated a strong correlation between BIRC6 mutations and the previously described immune response 2 signature that is associated with a poor prognosis. We further performed unbiased clustering of genetic alterations in these FL cases. We identified a cluster that was specifically enriched in BCL6 and TP53 alterations and was strongly associated with grade 3 FLs which are predicted to have poorer outcomes with low intensity therapies. We further examined the genetic profiles of 1001 DLBCLs in comparison to this cohort of FLs. Our data indicate a continuum of highly overlapping genetic alterations with DLBCL displaying more complex patterns that included alterations in MYC, TP53 and CDKN2A (mainly copy number losses), indicating shared pathogenetic mechanisms underlying FL and DLBCL, particularly those germinal center B cell origin. Disclosures Koff: Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Lymphoma Research Foundation: Research Funding; American Association for Cancer Research: Research Funding. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Gang:ROCHE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Flowers:AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Neff:Enzyvant: Consultancy; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fedoriw:Alexion Pharmaceuticals: Other: Consultant and Speaker. Reddy:Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy; Abbvie: Consultancy. Mason:Sysmex: Honoraria. Behdad:Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Speaker. Burton:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dave:Data Driven Bioscience: Equity Ownership.
- Published
- 2019
16. Analysis of Factors Predictive of Risk of Transformation and Time to Transformation in Patients (pts) with Mantle Cell Lymphoma - Cohort Study of 369 Patients
- Author
-
Hun Ju Lee, Jorge E. Romaguera, Keyur P. Patel, Changying Jiang, Ahmad Ghorab, Richard E. Champlin, Guofang Xu, Michael L. Wang, Loretta J. Nastoupil, Swaminathan P. Iyer, Fredrick B. Hagemeister, Nathan Fowler, Chi Young Ok, Preetesh Jain, Guangchun Han, Rashmi Kanagal-Shamanna, Jason R. Westin, Krystle Nomie, Lucy Navsaria, Prajwal Boddu, Luis Fayad, Linghua Wang, Shaojun Zhang, Sairah Ahmed, Guilin Tang, Shaoying Li, Pan Tinsu, Selvi Thirumurthi, Graciela M. Nogueras González, Sattva S. Neelapu, and Gonzalez-Pagan Omarya
- Subjects
Oncology ,medicine.medical_specialty ,Univariate analysis ,business.industry ,Immunology ,Cell Biology ,Hematology ,Logistic regression ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Transformation (genetics) ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Ibrutinib ,Medicine ,Vindesine ,Mantle cell lymphoma ,business ,health care economics and organizations ,medicine.drug ,Cohort study - Abstract
Introduction: A fraction of pts with classic variant MCL can transform to an aggressive histology (blastoid/pleomorphic) MCL. Outcomes of transformed pts are inferior to that of denovo blastoid variant MCL and classic variant MCL who never transformed (CNT) Jain P et al ASH 2018. Application of routinely available clinical variables at initial diagnosis to predict the future risk for transformation or time to transformation is an unmet need in MCL. Methods: We analyzed charts from 369 pts with MCL (293 were CNT and 76 were transformed MCL). Statistical analysis was performed from baseline pt characteristics collected from the time of initial diagnosis in CNT group and at the time of initial diagnosis of classic variant MCL who later transformed (t-MCL). Time to transformation (TTT) was calculated from initial diagnosis to the date of transformation in those who transformed and last follow up in those who never transformed. Univariate and multivariate logistic regression modeled the risk of transformation. Classification and regression tree (CART) analysis was performed to identify optimal cut off in categorical variables predictive of TTT. Results: Among the 369 pts, the median age was 62 yrs (range 34-90), 79% were males. Ki-67% values were available in 133 pts (36% of total) and median Ki-67% was 25% (range 1-80). 84% had initial bone marrow involvement and 12% had leukemic phase at diagnosis. The median follow up was 58.5 months and the median overall survival (OS) was 94.8 months and 47% were alive at the time of this analysis. Compared to pts in the CNT group, pts in t-MCL group exhibited differences in following baseline characteristics - higher values of median Ki-67% (30% vs 20% in t-MCL; p=0.04), higher LDH levels, higher proportions of pts with high risk simplified MIPI risk score, leukemic phase at initial diagnosis, complex karyotype and lower hemoglobin and lower proportion of pts achieving complete remission (CR) after first line treatment (78% in t-MCL vs 86% in CNT). In addition, first line treatments received by both groups were similar - R-HCVAD based, R-chemo based, ibrutinib based, chemotherapy alone and miscellaneous. Logistic regression model showed factors associated with the risk of transformation. In univariate analysis, higher risk was significantly associated with Ki-67% as a continuous variable - OR 1.03 (95% CI 1.01-1.05; p=0.006), leukemic phase at diagnosis, high risk MIPI score, complex cytogenetics. First line treatment with ibrutinib compared to R-HCVAD, autologous stem cell transplant SCT at any time point and higher number of nodal sites were associated with decreased risk of transformation. In multivariate analysis (MVA), higher number of nodal sites and SCT were associated with decreased risk of transformation. The median time to transformation in months for those who transformed was 39 (range 5-240 months) while in CNT it was 51 months (1-257 months). We further identified that incremental Ki-67% was significantly associated with TTT and OS (Figure-1A-B). Using CART analysis we identified Ki-67% ≥60 is significantly associated with shorter TTT (HR, 6.26; 95% CI 2.58-15.21; p Conclusions: This is the first analysis showing an association of routinely available clinical variables in determining risk for transformation of MCL and TTT. Routinely available variables such as incremental Ki-67%, LDH levels, number of nodal sites, ibrutinib based treatments, SCT, CR after first line treatment and leukemic phase at diagnosis reliably predicted for time to transformation in MCL. Disclosures Lee: Seattle Genetics, Inc.: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding. Nastoupil:Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Champlin:Sanofi-Genzyme: Research Funding; Actinium: Consultancy; Johnson and Johnson: Consultancy. Neelapu:Cellectis: Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; BMS: Research Funding; Acerta: Research Funding; Incyte: Consultancy; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Cell Medica: Consultancy; Karus: Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Allogene: Consultancy. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria; MoreHealth: Consultancy, Equity Ownership; Pharmacyclics: Honoraria, Research Funding; Acerta Pharma: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding.
- Published
- 2019
17. MYC Expression in Systemic Anaplastic Large Cell Lymphoma: Clinicopathologic and Prognostic Features of 70 Patients
- Author
-
Kirill A. Lyapichev, Roberto N. Miranda, L. Jeffrey Medeiros, C. Cameron Yin, Carlos E. Bueso-Ramos, Swaminathan P. Iyer, M. James You, Sergej Konoplev, Guilin Tang, Shaoying Li, and Jie Xu
- Subjects
CD30 ,biology ,business.industry ,CD3 ,Immunology ,Cell Biology ,Hematology ,Gene rearrangement ,medicine.disease ,Biochemistry ,Exact test ,hemic and lymphatic diseases ,Cancer research ,biology.protein ,Medicine ,T-cell lymphoma ,Immunohistochemistry ,business ,Diffuse large B-cell lymphoma ,Anaplastic large-cell lymphoma - Abstract
Background: Dysregulation of MYC has oncogenic potential. It has been reported that MYC dysregulation (gene rearrangement, increased copy number, and protein overexpression) predicts poorer prognosis in patients with diffuse large B cell lymphoma. Systemic anaplastic large cell lymphoma (ALCL) is a T cell lymphoma with strong, uniform CD30 expression. Although some in vitro studies showed MYC signaling is essential for the survival of ALCL cells, the possible role of MYC expression in the clinicopathologic features and outcome of ALCL patients has not been reported. Method: We studied 70 patients with systemic ALCL (31 ALK+ and 39 ALK-negative) in whom MYC expression was assessed by immunohistochemistry at the time of diagnosis. The positive cut-off value for MYC was > 40%. The clinicopathologic features and outcome of patients with MYC+ tumors were compared to patients with MYC-negative tumors in both the ALK+ and ALK-negative ALCL groups, respectively. Fisher's exact test was used to compare the clinicopathologic features of the MYC+ and MYC-negative groups. Overall survival (OS) was analyzed using the Kaplan-Meier method and compared using the log-rank test. Results: There was no difference in the frequency of MYC positivity rate between ALK+ vs. ALK-negative ALCL (39% vs 26%, p = 0.30). In ALK+ ALCL, patients with a MYC+ tumor more often had an increased serum LDH level than those with a MYC-negative tumor (86% vs 25%, p = 0.04), and they tended to have a higher frequency of common morphology (100% vs 68%, p = 0.059). No significant difference was observed in the treatment between MYC+ vs MYC-negative groups in patients with ALK+ ALCL (p > 0.05). MYC expression was associated with shorter OS in patients with ALK+ ALCL (median survival 12.8 months vs undefined, p = 0.038; Figure). In ALK-negative ALCL, patients with a MYC+ tumor were more often older (median age 66.5 years, range 46-95 years) than those with a MYC-negative tumor (median age 56 years, range 21-77 years) (p = 0.02); they also tended to have less advanced (stage III to IV) disease (43% vs 85%, p = 0.05). ALK-negative MYC+ ALCL showed less frequent CD3 expression (20% vs 67%, p = 0.02) and a trend of decreased CD4 expression (67% vs 96%, p = 0.05), compared to their ALK-negative MYC-negative counterparts. There was no significant difference in treatment between MYC+ vs MYC-negative groups in patients with ALK-negative ALCL (p > 0.05). MYC expression was not associated with OS in patients with ALK-negative ALCL (p = 0.35). Conclusions: MYC expression is independent of ALK status in ALCL and appears to have distinct clinicopathologic and prognotstic roles in ALK+ vs ALK-negative ALCL. In ALK+ ALCL, MYC expression is associated with an elevated serum LDH level and shorter OS. In ALK-negative ALCL, MYC expression is associated with older age and less frequent CD3 expression, but does not predict OS. These data suggest that MYC expression in ALK+ ALCL may be a poor prognostic factor. Figure Disclosures Bueso-Ramos: Incyte: Consultancy.
- Published
- 2019
18. CD138− plasma cell myeloma
- Author
-
Shaoying Li and Wen Shuai
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Immunology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,DNA Mutational Analysis ,Biopsy ,Plasma Cell Myeloma ,medicine ,Multiple myeloma ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Cytoplasm ,Cancer research ,Bone marrow ,Stem cell ,business ,030215 immunology - Abstract
[Figure][1] A 69-year-old man with a history of CD138− plasma cell myeloma (PCM) who received chemotherapy regimens and stem cell transplant presented for bone marrow biopsy, which revealed sheets of atypical plasma cells with abundant amphophilic cytoplasm, occasional binucleation, and
- Published
- 2019
19. Outcomes of Patients with Limited-Stage Aggressive Large B-Cell Lymphoma with MYC Rearrangement with and without BCL2 and/or BCL6 Rearrangements: A Retrospective Analysis from 15 US Academic Centers
- Author
-
Adam J. Olszewski, Francisco J. Hernandez-Ilizaliturri, David Peace, Anshu Giri, Brian T. Hill, Daniel J. Landsburg, Joanna C. Zurko, Shalin Kothari, Julie M. Vose, Kris Attwood, Luu Q. Pham, Michael C. Churnetski, Adrienne Groman, L. Jeffrey Medeiros, Ranjana H. Advani, Frederick Lansigan, Madelyn Burkart, Kami J. Maddocks, Sarah S Lee, Emma Rabinovich, Timothy F. Burns, David A. Bond, Reem Karmali, Yang Liu, Brian T. Hess, Pallawi Torka, Emily C. Ayers, Jonathon B. Cohen, Amitkumar Mehta, Shaoying Li, and Stefan K. Barta
- Subjects
education.field_of_study ,medicine.medical_specialty ,business.industry ,Radiation field ,Immunology ,Population ,Complete remission ,Cell Biology ,Hematology ,Stage ii ,CNS Prophylaxis ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Institutional research ,030220 oncology & carcinogenesis ,Family medicine ,Retrospective analysis ,Medicine ,business ,education ,Bristol-Myers ,030215 immunology - Abstract
Introduction: Patients (pts) with limited stage (LS) aggressive large B-cell lymphoma (ALBCL) comprise 30-40% of ALBCLs and are usually treated with R-CHOP with or without consolidative involved field radiation therapy (IFRT). In pts with ALBCL, cytogenetic studies have identified a subset with high-risk disease who harbor MYC rearrangement (MYC-R) with or without BCL2 (BCL2-R) and/or BCL6 (BCL6-R) rearrangements. This has led to the adoption of intensive induction strategies in this population; however, it is unclear if such an approach is necessary in limited stage disease. Methods: We conducted a multi-center (15 US academic centers) retrospective study of MYC-R LS-ALBCL pts with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) morphology. LS was defined by stage I and II confined to a single radiation field as determined by the treating center. Pts diagnosed between 1/1/2005 and 3/1/2017 were included. All pts received either R-CHOP or more intensive immuno-chemotherapy (IIC) (i.e. R-DA-EPOCH, R-hyperCVAD/MA, or R-CODOX-M/IVAC) with or without IFRT. Baseline demographic, clinical, laboratory, pathology and outcomes data was collected by retrospective chart review. Stage-modified IPI (sm-IPI) score was calculated [stage II (vs 1), age >60, elevated LDH, and ECOG performance status ≥ 2]. Differences in overall response rate (ORR), complete remission (CR) rate, 2-year progression-free survival (PFS) and overall survival (OS) were compared in pts treated with R-CHOP vs IIC and in pts treated with IFRT vs no IFRT. Results: A total of 142 pts with MYC-R LS-ALBCL were identified, of which 105 fulfilled the inclusion criteria. Baseline characteristics included: median age 65 yrs (range 21-85), 66% male; 14% stage I, 32% stage IE, 28% stage II, 26% stage IIE disease; 17% bulky, 58% extra-nodal, 15% transformed disease, 40% elevated LDH. The majority of pts (70%) had germinal center B-cell phenotype. Eighty-two pts had data on BCL2-R and BCL6-R, of which 41 (50%) had double-hit lymphoma (DHL), including 4 pts with triple-hit lymphoma. Forty-five pts (43%) received R-CHOP, of which 56% had IFRT. Sixty pts (57%) received IIC, of which 42% had IFRT. R-DA-EPOCH was the most common IIC regimen used (85%), followed by R-hyperCVAD/MA (12%). Age (p=0.38), stage (p=0.32), extra-nodal disease (p=0.84), LDH (p=0.09), sm-IPI (p=0.24), morphology (p=0.44) and double-hit status (p=1.00) were similar between pts receiving R-CHOP and IIC. Median no. of cycles (NOC) (6 vs 6) and proportion of pts who received IFRT (56% vs 42%, p=0.17) did not differ in the 2 groups. Median NOC were lower in IFRT vs no IFRT group (4 vs 6; p=0.02). Pts receiving IIC (vs. R-CHOP) were more likely to undergo CNS prophylaxis (CNS-P) (75% vs 29%, p ORR was 90% (83% CR, 7% PR). Pts with DHL were less likely to achieve a CR compared to pts with MYC-R only (73% vs 98%; p=0.011). CR rate was higher in the IFRT vs no-IFRT group (92% vs. 75%, p=0.028). In the 27 pts who had relapsed/refractory disease, distant relapses were more common in the IFRT vs no-IFRT group (87% vs 33%, p=0.007). Median follow-up was 3.2 yrs; 35 (33%) pts progressed or died. Of the 23 deaths, 15 were due to progressive lymphoma, 1 due to treatment-related toxicity and 7 due to unrelated causes. 2-year PFS and OS were 78% and 86% for the entire cohort and 72% and 82% respectively for DHL pts. Sm-IPI ≥ 2 (HR: 2.81, p=0.02) and age ≥ 70 (HR: 4.07, P Conclusions: Outcomes of MYC-R LS-ALBCL pts are excellent with 2-year PFS and OS of 78% and 86% respectively. There was no benefit of choosing IIC over R-CHOP or using CNS prophylaxis in pts with MYC-R LS-ALBCL and LS-DHL in our study. While IFRT was effective in inducing CRs and preventing local relapses, distant relapses limited its benefit. Pts with LS-DHL had lower CR rates with similar PFS and OS when compared to those with MYC-R as the sole cytogenetic abnormality. Longer follow up is needed to assess the impact of upfront treatment strategies on late relapses. Disclosures Landsburg: Takeda: Consultancy; Curis: Consultancy, Research Funding. Maddocks:Teva: Honoraria; AstraZeneca: Honoraria; Pharmacyclics/Janssen: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; BMS: Research Funding. Advani:Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Cell Medica: Other: Consultancy/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Celgene: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Gilead/Kite: Other: Consultancy/Advisory Role; Autolus: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Agensys: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Infinity: Other: Institutional Research Support; Millenium: Other: Institutional Research Support. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Vose:Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria; Roche: Honoraria; Epizyme: Honoraria; Kite Pharma: Research Funding; Celgene: Research Funding; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Acerta Pharma: Research Funding; Legend Pharmaceuticals: Honoraria. Cohen:Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Mehta:Seattle Genetics: Research Funding; Kite: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Merck: Research Funding; Spectrum: Consultancy; Epizyme: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Incyte: Research Funding; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy; Carevive: Other: Patient engagement; Medpage: Other: Medical website. Olszewski:Spectrum Pharmaceuticals: Consultancy, Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding. Hill:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees.
- Published
- 2018
20. Outcome of Patients with Aggressive B Cell Lymphomas Who Receive Second-Line Salvage Immunochemotherapy Following Treatment Failure of Intensive First-Line Immunochemotherapy
- Author
-
Brian T. Hess, Pallawi Torka, Michael C. Churnetski, Anshu Giri, Emily C. Ayers, Dipenkumar Modi, Jonathon B. Cohen, Adam J. Olszewski, Angel Mier Hicks, Kevin A. David, Helen Ma, Kami J. Maddocks, Rawan Faramand, Sarit Assouline, Nishitha Reddy, Samuel Cytryn, Bita Fakhri, Lori A. Leslie, Nina D. Wagner-Johnston, Yang Liu, David A. Bond, Reem Karmali, Shaoying Li, Brad S. Kahl, Stefan K. Barta, Catherine Diefenbach, Sunita Nathan, Dhruvika Mukhija, L. Jeffrey Medeiros, Madeira Curry, Christina Howlett, Radhakrishnan Ramchandren, Julio C. Chavez, Victor M. Orellana-Noia, Craig A. Portell, Jennifer E Amengual, Ashwin Chandar, Amir Behdad, Daniel J. Landsburg, and Brian T. Hill
- Subjects
medicine.medical_specialty ,business.industry ,First line ,Immunology ,Disease progression ,Early Relapse ,Cell Biology ,Hematology ,Biochemistry ,Treatment failure ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Second line ,030220 oncology & carcinogenesis ,Family medicine ,Partial response ,medicine ,business ,Complete response ,030215 immunology - Abstract
Introduction: Salvage immunochemotherapy (IC), followed by high-dose chemotherapy with autologous stem cell transplantation if chemosensitive is standard-of-care second-line (2L) therapy (tx) for fit patients (pts) with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) when treated with first-line (1L) R-CHOP as shown in the CORAL study. Outcomes following receipt of salvage IC in the 2L setting for pts with DLBCL or high grade B cell lymphoma/B cell lymphoma unclassifiable (HGBL/BCLU) receiving intensive 1L tx remain unknown, and may be worse than those reported in CORAL given prior exposure to higher-dose IC in 1L setting. Here we report the results of a multicenter retrospective analysis of R/R DLBCL and HGBL/BCLU pts treated with intensive 1L tx who receive standard salvage 2L tx. Methods: Inclusion criteria were histologic diagnosis of DLBCL or HGBL/BCLU, R/R disease following 1L tx with R-EPOCH, R-HyperCVAD or R-CODOX-M/IVAC and receipt of 2L tx with R-ICE, R-DHAP, R-DHAC, R-ESHAP or R-GDP. Exclusion criteria were HIV positivity, post-transplant lymphoproliferative disorder, prior chronic lymphocytic leukemia and inadequate data. Therapy was given at the discretion of the treating physician. Progression free survival (PFS) was defined as the interval between time of first relapse or primary refractory disease and disease progression, change in therapy if no disease response or last follow-up in remission, and overall survival (OS) between time of first relapse or primary refractory disease and death or last follow-up while alive. Pts were treated from 2007-2017 and data were censored on 10/15/17. Results: A total of 195 pts treated at 20 US and Canadian academic medical centers were included. Clinicopathologic characteristics at time of R/R disease were 39% age >60 years, 62% male, 77% stage III-IV, 72% elevated LDH, 24% bone marrow (BM) involvement, 28% B symptoms present, 44% extranodal (EN) disease at >1 site, 19% ECOG performance status (PS) >1, 49% with International Prognostic Index score (IPI) ≥3, 46% HGBL/BCLU histology, 49% Ki67 ≥90%, and 61% germinal center (GCB) cell of origin (COO) by Hans algorithm. Of pts with available fluorescence in situ hybridization (FISH) data, 51%, 45% and 30% demonstrated MYC, BCL2 and BCL6 rearrangements (-R), respectively, and 37% were double hit lymphoma (DHL). Tx received in 1L were R-EPOCH in 82%, R-HyperCVAD in 16% and R-CODOX-M/IVAC in 2% of pts. R-ICE was received by 64% and other platinum-containing regimens by 36% as 2L tx. Most (86%) pts relapsed within 12 months (mo) of completion of 1L tx (early) and 58% of pts had primary refractory disease. For all pts, the median length of follow-up was 25.0 mo with a median PFS of 3.0 mo and median OS of 8.0 mo. Overall response rate to 2L tx among all pts was 44% (23% complete response [CR] and 21% partial response [PR]), and 48% with progressive disease. Pts achieving CR had significantly longer median PFS (32.0 vs 4.0 mo, p = 0.0001) and OS (not reached vs 13.0 mo, p = 0.0004) as compared to pts achieving PR. In pts who achieved CR or PR following 2L tx, 64% received consolidative transplant (42 autologous and 13 allogeneic) and achieved a median PFS and OS of 18.3 mo and 62.0 mo, respectively. As compared to pts relapsing ≥12 mo after completion of 1L tx (late), pts relapsing early were less likely to achieve CR (17% vs. 61%, p=0.0001) and experienced significantly shorter median PFS (2.8 vs. 23.0 mo, p1 site, B symptoms, ECOG PS >1 and Ki67 ≥90%, but not BCL2-R, demonstrated a statistically significant increased HR for death. Multivariate analysis demonstrated only early relapse to have a statistically significant increased HR for progression (HR 2.47, p=0.024) and death (HR 5.90, p=0.001). Conclusion: Relapse Figure. Figure. Disclosures Maddocks: Pharmacyclics: Research Funding; BMS: Research Funding; Teva: Honoraria; AstraZeneca: Honoraria; Novartis: Research Funding; Pharmacyclics/Janssen: Honoraria; Merck: Research Funding. Wagner-Johnston:Novartis: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Merck: Research Funding; JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees. Karmali:Gilead: Speakers Bureau; AstraZeneca: Speakers Bureau. Kahl:Genentech: Consultancy; Juno: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Acerta: Consultancy; CTI: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Cohen:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reddy:MEI Pharma: Research Funding. Ramchandren:Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding. Diefenbach:Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; Trillium: Research Funding; Millenium/Takeda: Research Funding; Denovo: Research Funding; Acerta: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy. Olszewski:TG Therapeutics: Research Funding; Genentech: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Hill:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Assouline:Roche: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Landsburg:Curis: Consultancy, Research Funding; Takeda: Consultancy.
- Published
- 2018
21. Plasma cell leukemia presenting as 'lymphocytosis'
- Author
-
Shaoying Li and Jie Xu
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Lymphocytosis ,Anemia ,Immunology ,H&E stain ,Magnification ,Biochemistry ,Stain ,Leukemia, Plasma Cell ,Diagnosis, Differential ,03 medical and health sciences ,Antigens, CD ,Antigens, Neoplasm ,Biopsy ,medicine ,Humans ,Aged ,Plasma cell leukemia ,medicine.diagnostic_test ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Bone marrow ,medicine.symptom ,business - Abstract
[Figure][1] A 70-year-old man presented with anemia and “lymphocytosis” (panel A; Wright-Giemsa stain, original magnification ×1000). Bone marrow biopsy revealed diffuse small neoplastic cells (panel B; hematoxylin and eosin stain, original magnification ×200) morphologically similar
- Published
- 2018
22. Chemotherapy-Free Induction with Ibrutinib-Rituximab Followed By Shortened Cycles of Chemo-Immunotherapy Consolidation in Young, Newly Diagnosed Mantle Cell Lymphoma Patients: A Phase II Clinical Trial
- Author
-
Steven Y. Huang, Francesco Turturro, Jorge E. Romaguera, Luis Fayad, Hun Ju Lee, Fredrick B. Hagemeister, Selvi Thirumurthi, Alicia Addison, Michael Wang, Wendy Chen, Jason R. Westin, Felipe Samaniego, Kimberly Hartig, Onyeka Oriabure, Makhdum Ahmed, Krystle Nomie, Hubert H. Chuang, Shaoying Li, Laura T Lam, Liang Zhang, and Maria Badillo
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cyclophosphamide ,Immunology ,Phases of clinical research ,Neutropenia ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Progression-free survival ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Surgery ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Rituximab ,Mantle cell lymphoma ,business ,Febrile neutropenia ,medicine.drug - Abstract
Introduction: Mantle cell lymphoma (MCL) is a rare and incurable subtype of B-cell lymphoma. Intense chemo-immunotherapy with 8 cycles of Rituximab-HyperCVAD alternating with Rituximab-Methotrexate-Ara C is associated with an overall survival of 10.7 years but the 10-year cumulative incidence of therapy-related myeloid neoplasm was 6.2%. The ibrutinib-rituximab combination has produced durable responses in 88% of patients with relapsed and refractory MCL with acceptable toxicity. This gives rise to a "Window" of opportunity to use chemotherapy-free induction with ibrutinib plus rituximab followed by fewer cycles of chemo-immunotherapy consolidation in young and fit patients with newly-diagnosed, untreated MCL. Methods: Enrolment began in June 2015 for a Phase II single-center clinical trial consisting of an initial chemotherapy-free phase (window) of ibrutinib and rituximab combination treatment in Part 1 until best response, followed by a shortened course of intense chemo-immunotherapy in Part 2 among young newly diagnosed MCL patients of ≤65 years. The primary objective was to evaluate the response rate of ibrutinib plus rituximab. The secondary objectives were to evaluate the progression free survival (PFS) of ibrutinib plus rituximab after consolidation with a shortened number of cycles of intense chemo-immunotherapy, and to further evaluate the toxicity profile. Ibrutinib is dosed at 560 mg orally, daily, continuously. Rituximab is dosed at 375 mg/m2 IV weekly x 4 during cycle 1 (28 days cycle), then day 1 of cycles 3-12. Intense chemo-immunotherapy consists of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD); alternating every 28 days with rituximab plus high-dose methotrexate-Ara C. If in complete remission (CR) after initial ibrutinib and rituximab treatment, a total of 4 additional treatments of intense chemo-immunotherapy are given. If the patient is in partial response or progression, and if responding to intensive chemo-immunotherapy, a total of 2 cycles of chemo-immunotherapy therapy are administered beyond achievement of CR. Results: As of August 2, 2016, we have completed the target enrolment by accruing 50 out 50 patients with newly-diagnosed untreated MCL. Forty one (n=41) patients have begun treatment and 36 are evaluable for response. Of the 36 evaluable patients, overall response rate (ORR) to Part 1 alone (Ibrutinib plus rituximab) is 100% (n=36) with PR in 28% (n=10) and CR in 72% (n=20). Nineteen 19 patients have completed both Part 1 (ibrutinib and rituximab) and Part 2 (chemo-immunotherapy). The ORR to both Part 1 and Part 2 (n=19) was 100% and was equal to the CR rate (100%, n=19), i.e. all have achieved a CR to Part 1 and Part 2. Toxicities are recorded as the number of patients experiencing a certain adverse event. Regardless of their relation to study drug in Part 1, the most common grade 1-2 non-haematological (non-heme) adverse effects (AEs) are fatigue (n=40), diarrhea (n=25), rash (n=24), myalgia (n=22), oral mucositis (n=17), peripheral neuropathy (n=15), nausea (n=14), blurred vision (n=14), edema (n=13), constipation (n=12), headache (n=11), dry eyes (n=9), dizziness (n=9) and watery eyes (n=6). Grade 3 non-heme AEs included fatigue (n=3), nausea (n=0), rash (n=1), pleural effusion (n=1), infection (n=2) and dyspnea (n=1). There was no grade 4 or grade 5 non-heme toxicities in Part 1. In part 2, common grade 1-2 hematological (heme) AEs was anemia (n=13). Grade 3-4 haematological AEs included neutropenia (n=2), ALT increase (n=1) and febrile neutropenia (n=1). In Part 2, there was no grade 5 hematologic toxicity. The toxicity after intensive immune-chemotherapy in shortened cycles are much improved compared to historical controls but longer follow-up is needed. Conclusions: Preliminary data indicate that the chemotherapy-free induction with ibrutinib and rituximab in newly diagnosed, young MCL patients was efficacious and well-tolerated. This unprecedented efficacy and safety may provide a window of opportunity for less chemo-immunotherapy needed for consolidation. Table Preliminary findings form the Window Study: a phase II clinical trial Table. Preliminary findings form the Window Study: a phase II clinical trial Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding.
- Published
- 2016
23. CD5 Negative Mantle Cell Lymphoma: Clinicopathologic Correlations and Outcome in 58 Cases
- Author
-
Shaoying Li, Pei Lin, Annapurna Saksena, C. Cameron Yin, Yuan Miao, Jingyi Li, L. Jeffrey Medeiros, and Michael Wang
- Subjects
Oncology ,medicine.medical_specialty ,Vincristine ,business.industry ,Immunology ,Induction chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,Log-rank test ,Transplantation ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Rituximab ,Mantle cell lymphoma ,business ,Progressive disease ,Survival analysis ,medicine.drug - Abstract
Introduction: Mantle cell lymphoma (MCL) is a B-cell neoplasm that has a characteristic immunophenotype of being positive for CD5, B-cell antigens and cyclin D1. A small subset of cases of MCL can be negative for CD5, approximately 5% in the literature. The clinicopathologic features and prognosis of patients with CD5-negative MCL are poorly characterized. Here, we study a group of patients with CD5- MCL and compare them with a group patients with CD5+ MCL. Methods: From a total of 270 cases of MCL accessioned from 2004-2015, 58 CD5- cases (study group) and 212 CD5+ cases (control group) were identified. All cases of MCL were positive for cyclin D1 by immunohistochemistry and, in most patients, CCND1-IGH was shown FISH. Cases negative for CD5 were assessed by flow cytometry and/or immunohistochemistry. Fisher exact test was utilized to analyze differences between the CD5- and CD5+ groups. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazards model analyses for OS and PFS were performed (SPSS 22 software). A P-value of less than 0.05 was considered statistically significant. Results: The CD5- group included 39 men and 19 women with a median age of 66 years (range, 36- 88 years) at time of diagnosis. The CD5- and CD5+ groups shared overlapping clinicopathological features, but CD5- cases showed a lower percentage of men (P=0.006) than CD5+ cases. Treatment information was available for 50 patients. Twenty-nine (58%) patients were treated initially with R-Hyper CVAD therapy (rituximab, fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high dose methotrexate and cytarabine). Seventeen (34%) patients were treated initially with less aggressive therapy: 7 with R-CHOP; 8 had other rituximab-based chemotherapy regimens; 2 received rituximab as a single agent. Four patients (8%) were observed without therapy. After induction, 34 patients achieved complete remission (CR), 5 patients achieved partial remission (PR), 6 patients showed no response (NR) or progressive disease (PD), and 5 patients lost follow-up. Ten patients also underwent stem cell transplantation (SCT): 5 patients received allogeneic SCT, the other 5 autologous SCT. With a median follow-up of 45.7 months (range, 2.0-174.3 months), 13 of 56 (23.2%) patients died, 43 of 56 (76.8%) patients were alive at last follow-up, and the rest of 2 patients lost follow up. The induction chemotherapy regimens and CR and PR rate were not significantly different between the CD5- and CD5+ groups (p>0.05). Survival analysis showed patients with CD5- MCL had a tendency for longer OS (Figure 1A, P=0.078). Further analysis showed that lack of CD5 expression predicted a superior OS in a few subsets of MCL patients defined with 1) normal WBC count (p=0.049); 2) Stage I/II disease (p=0.046); 3) Low/intermediate MIPI (p=0.041) and 4) Ki67≥30% (at a borderline p value of 0.05). Patients with CD5- MCL also showed a significantly longer progression-free survival (PFS) (Figure 1B, P=0.01). Absence of CD5 expression was associated with a better PFS in MCL patients with advanced disease (stage III-IV) (P=0.035), a normal leukocyte count (P=0.018), a normal serum lactate dehydrogenase level (P=0.046), classical morphology (P=0.029), and low/intermediate MIPI (p=0.0004). Multivariate Cox regression analysis revealed that MIPI was the only independent prognostic factor for both OS and PFS (P=0.026 and P=0.001 respectively) and CR/PR also predict a better OS (P=0.004) in CD5- MCL patients. Conclusion: The clinicopathologic features were similar between patients with CD5- MCL and those with CD5+ MCL, except that less men in the CD5- MCL group. Lack of CD5 expression was associated with a favorable PFS in MCL patients. Recognizing this subgroup of CD5- MCL has not only a diagnostic significance, but also a prognostic significance. Figure Figure. Disclosures Wang: Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Onyx: Research Funding.
- Published
- 2016
24. MYC Copy Number Aberrancies Predict a Worse Prognosis in Patients with Diffuse Large B-Cell Lymphoma
- Author
-
Nishitha Reddy, Adam C. Seegmiller, Jie Xu, Pei Lin, Guilin Tang, Jason R. Westin, Parth Desai, L. Jeffrey Medeiros, Wei Wang, Shaoying Li, Andrés E. Quesada, Roberto N. Miranda, and C. Cameron Yin
- Subjects
Oncology ,medicine.medical_specialty ,Immunology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,In patient ,medicine.diagnostic_test ,business.industry ,Cell Biology ,Hematology ,BCL6 ,medicine.disease ,Chemotherapy regimen ,Lymphoma ,Exact test ,030220 oncology & carcinogenesis ,Immunohistochemistry ,business ,Diffuse large B-cell lymphoma ,030215 immunology ,Fluorescence in situ hybridization - Abstract
Introduction: It is known that patients with double hit (DHL) and triple hit lymphoma (THL) have a significantly worse prognosis compared to patients with diffuse large B-cell lymphoma (DLBCL) without MYC rearrangement (MYC-R). Some studies have shown that DLBCL patients with MYC rearrangement only (single hit lymphoma; SHL) also have a poor prognosis similar to those with DHL/THL. However, it is not uncommon for fluorescence in situ hybridization (FISH) to detect extra copies (EC) of MYC, BCL2 or BCL6 in the absence of rearrangement. The potential role of these extra copies (EC) on survival has not been fully explored. In the current study, we focused on the prognostic significance of MYC-EC in comparison with MYC-R in patients with de novo DLBCL treated with rituximab-chemotherapy. Materials and Methods: A total of 664 de novo DLBCL cases with MYC/8q24, BCL2/18q21 and BCL6/3q27status confirmed by FISH and/or karyotype from 2010-2015 were included. MYC SHL, DHL and THL were identified if they had rearrangements of MYC only, both MYC and BCL2 or BCL6, or concurrent MYC, BCL2, and BCL6, respectively. Positive expression for MYC or BCL2 by immunohistochemistry was defined by >40% and >50% staining in the lymphoma cells, respectively.Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test.Fisher's exact test was used to compare the clinicopathologic features.Statistical analysis was performed using SPSS 23 software. Results: 105 DLBCL had MYC-R, 77 had MYC-EC, and 482 had no MYC abnormality (MYC-NL). The 105 MYC-R cases included 28 SHL, 45 DHL (39 MYC/BCL2 and 6 MYC/BCL6 DHL), 11 THL, and 21 with unknown BCL2 or BCL6 status. Overall, the clinicopathologic features including overall survival (OS) were similar among SHL, DHL, and THL patients (Figure 1A, p=0.92). Patients with DLBCL harboring MYC-R had more aggressive clinicopathologic features than those with MYC-EC or MYC-NL (p Although both the MYC-R and MYC-EC groups demonstrated a worse OS than MYC-NL patients (p By multivariate analysis, MYC-R (HR=2.55, p=0.0001) but not MYC-EC was an independent prognostic factor in de novo DLBCL patients. Conclusion: Patients with DLBCL harboring extra copies of MYC have clinicopathologic features more in common to DLBCL patients with normal MYC status than those with MYC rearrangement. The OS in patients with DLBCL harboring extra copies of MYC was significantly worse than in DLBCL patients without MYC abnormality; however, it was not as poor as that seen in patients with DLBCL with MYC-R. Compared to R-CHOP, intensive induction regimens (R-EPOCH & R-Hyper-CVAD) showed only a trend towards better prognosis in DLBCL patients with MYC rearrangement or extra copies. Figure 1 Figure 1. Disclosures Westin: Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees. Reddy:GILEAD: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees.
- Published
- 2016
25. Mimics of megakaryocytes: giant bizarre myeloma cells
- Author
-
Shaoying Li and Huifei Liu
- Subjects
Male ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,Plasma Cells ,Immunology ,Bone Marrow Examination ,Cell Biology ,Hematology ,Anatomy ,Middle Aged ,Biology ,Giant Cells ,Biochemistry ,Bone marrow examination ,medicine.anatomical_structure ,Giant cell ,Biopsy ,medicine ,Humans ,Bone marrow ,Multiple Myeloma ,Megakaryocytes - Abstract
[Figure][1] The bone marrow (BM) biopsy (panel A; original magnification ×400 for all panels) from a 59-year-old man showed many giant cells we initially thought of as megakaryocytes (yellow arrowheads). Morphological features different from normal megakaryocytes included relatively high
- Published
- 2016
26. MYC/BCL2 Double Hit Lymphoma: What Really Matters
- Author
-
Zhuang Zuo, Shaoying Li, Guilin Tang, Annapurna Saksena, Roberto N. Miranda, C. Cameron Yin, Nishitha Reddy, L. Jeffrey Medeiros, Pei Lin, Adam C. Seegmiller, Parth Desai, Jeffrey L. Jorgensen, and Jie Xu
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,Immunology ,Follicular lymphoma ,Cell Biology ,Hematology ,Gene rearrangement ,Biology ,medicine.disease ,BCL6 ,Biochemistry ,Lymphoma ,International Prognostic Index ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,B-cell lymphoma ,Burkitt's lymphoma ,Diffuse large B-cell lymphoma - Abstract
Introduction: MYC/BCL2 double hit lymphoma (DHL), defined as a large B-cell lymphoma with concurrent MYC and BCL2 translocations, is the most common type of DHL. Although multiple studies focused on DHL have been published, several issues regarding impact on prognosis remain controversial including: 1) history of low grade B cell lymphoma; 2) morphology (diffuse large B-cell lymphoma [DLBCL] versus B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma [BCLU)]; 3) Absence or low expression of MYC or BCL2; 4) MYC translocation partner gene; and especially 5) most effective therapy. The aim of this study was to attempt clarify the prognostic importance of these factors in DHL. Methods: 157 patientsdiagnosed with MYC/BCL2 DHL between 2003 and April 2015 at two institutions were included in this study. MYC and BCL2 gene rearrangement were confirmed by FISH using a MYC breakapart probe and BCL2 and IGH dual color dual fusion probes. BCL6 /3q27gene status was tested either by FISH using breakapart probe or by karyotype. MYC partner gene was identified by karyotype. MYC/BCL2 DHL cases were identified if they had rearrangements of MYC and BCL2 but not BCL6 . Positive for MYC or BCL2 by immunohistochemistry was defined by >40% and >50% of lymphoma cells showed positive expression, respectively. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Fisher's exact test was used to compare the clinicopathologic features. Statistical analysis was performed using SPSS 23 software. Results : There were 103 men and 54 women with a median age of 61 years (range, 18-87). 110 patients had de novo disease and 47 patients had a history of low-grade B-cell NHL, mostly follicular lymphoma. The clinicopathologic features were similar (P>0.05) between patients with a history of low-grade B-cell NHL and patients with de novo NHL, and therefore analysis was performed on all 157 DHL cases. Using the 2008 WHO classification, there were 91 DLBCL, 61 BCLU, and 5 composite lymphoma (4 DLBCL + follicular lymphoma and 1 DLBCL + B-lymphoblastic lymphoma). 99% of cases had a germinal center B-cell immunophenotype by the Hans algorithm. MYC expression was observed in 39/47 (83%) and BCL2 in 129/141(91%) of cases. MYC and BCL2 dual expression was present in 34/46(74%) cases. Of the 39 cases assessed, the MYC translocation partner was IGH in 13, IG light chain in 19, and a non-IG gene in 7 cases. 144 patients had complete treatment information: 61 received the R-CHOP regimen initially, 31 R-EPOCH, 29 R-HCVAD, and 23 various other chemotherapy regimens. 39 patients also received stem cell transplant (SCT) including 31 autologous and 8 allogeneic. 62 patients reached complete remission (CR) after initial chemotherapy. The median overall survival was 19 months. In a univariate analysis that evaluated 17 clinicopathologic parameters including those mentioned in introduction, extranodal sites of disease, bone marrow involvement, CNS involvement, advanced stage, and high/high-intermediate International Prognostic Index score were associated with a worse overall survival (OS, P
- Published
- 2015
27. Differences in Outcome of Patients with Syncytial Variant Hodgkin Lymphoma (HL) Compared with Typical Nodular Sclerosis HL
- Author
-
Van T Nguyen, Tarsheen K. Sethi, David S. Morgan, Nishitha Reddy, John P. Greer, and Shaoying Li
- Subjects
Cancer Research ,medicine.medical_specialty ,Univariate analysis ,business.industry ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,Cell Biology ,Hematology ,medicine.disease ,Gastroenterology ,Chemotherapy regimen ,Biochemistry ,Oncology ,Nodular sclerosis ,ABVD ,B symptoms ,Median follow-up ,Internal medicine ,medicine ,Progression-free survival ,medicine.symptom ,business ,medicine.drug - Abstract
Introduction: Syncytial variant of nodular sclerosis HL (SV) is a well-described distinct pathologic entity characterized by prominent aggregates of Hodgkin/Reed- Sternberg cells in nodules separated by fibrous collagen bands. Despite its well-known morphologic description, little is known regarding the clinical behavior of the SV. Previous reports suggest that patients with SV often presented with B symptoms and advanced stage disease, however, large series defining the clinical outcome have not been reported so far. We systematically studied the clinical features and outcome of patients with SV and further compared them with patients with typical nodular sclerosis HL (t-NS). Patients and Methods: 167 adult patients (pts.) with Nodular Sclerosis HL were included in our analysis following institutional IRB approval. Differences between the two groups (SV vs. t-NS) were analyzed using Chi- square and t -Student tests. Statistical significance was set at P Results: Of the 167 patients, 43 were confirmed as SV based on morphology and immunophenotype. The median age at diagnosis was 31 yrs. (range: 18-75 yrs.) and 85 patients were male (51%). At diagnosis, 100% patients had an ECOG status of 0-1; 39 % had advanced stage disease (stage III and IV); and 48% had B symptoms. 23 % patients presented with bulky disease defined as a mass > 10 cm or a mediastinal mass >1/3 of thorax at T5-T6. 90% patients received ABVD as their initial treatment. The remaining were treated with Stanford V, MOPP or on a clinical trial. 37 % patients received radiation therapy. Furthermore, 63% patients with SV and relapsed disease were treated with high dose therapy followed by stem cell transplant (ASCT). In the SV vs. t-NS comparison, no statistically significant differences were observed between the two groups with regards to age, gender, stage at presentation, B symptoms, bulky disease or favorable features. The rate of complete response (CR) in the SV group was 74% vs. 87% in the t-NS group (P=0.05). Moreover, at a median follow up of 49 months, the median progression free survival (PFS) was inferior in the SV group (17.02 months) compared with the t-NS group (not reached) (P Discussion: In summary, our results suggest that SV was associated with a lower rate of complete response to standard ABVD chemotherapy +/- radiation and inferior PFS. Despite the high rate of relapse associated with SV, these patients can be salvaged with standard salvage regimens, ASCT or newer immunomodulatory agents and therefore not compromising OS. Our report suggests that patients with SV should be considered for novel combination immuno-chemotherapies to improve the rate of complete remission and subsequently avoid the need for ASCT. Figure 1. PFS in patients with SV vs. t-NS Figure 1. PFS in patients with SV vs. t-NS Figure 2. OS in patients with SV vs. t-NS Figure 2. OS in patients with SV vs. t-NS Disclosures Reddy: PCYC: Consultancy; ImmunoGen: Consultancy; Gilead: Other: Speaker; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding.
- Published
- 2015
28. MYC Gene Single Hit Diffuse Large B Cell Lymphoma Behaves Similarly To MYC/BCL2 Double Hit Lymphoma and Needs Similar Aggressive Treatment
- Author
-
Nishitha Reddy, Xuan J. Wang, and Shaoying Li
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,Immunology ,Cell Biology ,Hematology ,Gene rearrangement ,Biology ,medicine.disease ,BCL6 ,Biochemistry ,Chemotherapy regimen ,Lymphoma ,International Prognostic Index ,Median follow-up ,hemic and lymphatic diseases ,Internal medicine ,medicine ,B-cell lymphoma ,Diffuse large B-cell lymphoma - Abstract
Introduction Double hit diffuse large B cell lymphoma (DHL) is a heterogeneous group of high grade B-cell lymphoma with concurrent MYC and BCL2 (or other) gene rearrangements. It is well known that DHL has an aggressive clinical course, is resistant to standard R-CHOP chemotherapy, and confers a poor prognosis. Little is known about MYC single hit diffuse large B cell lymphoma (SHL) and how they behave and respond to therapy compared to MYC/BCL2 DHL. The aim of the study was to delineate the characteristics of MYC SHL and compare it to MYC/BCL2 DHL with regards to its clinicopathologic features, especially response to treatment and prognosis. Methods One hundred and fifteen patients diagnosed with large B cell lymphoma between September 2009 and June 2013 at our institution were included in this study. MYC and BCL2 gene rearrangement were confirmed by fluorescence in situ hybridization (FISH) using MYC breakapart probe and BCL2 and IgH dual color dual fusion probes, respectively. BCL6 gene rearrangement was revealed in a subset of cases either by FISH using breakapart probe or karyotype. MYC/BCL2 DHL cases were identified if they had rearrangements of MYC and BCL2. SHL cases were identified if they only had MYC rearrangement. Tumor cells were defined positive for MYC and BCL2 protein expression by immunostain if >40% and 50% of cells showed positive expression, respectively. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Fisher's exact test was used to compare the two groups. Results Of the 115 patients, 15 were MYC SHL and 24 were MYC/BCL2 DHL. Four DHL also had BCL6 rearrangement. All cases with karyotype available showed complex karyotype, both in SHL and DHL (Table 1). Of the 15 SHL patients, 9 were male and 6 were female with a median age of 63 years (range 36-78) at diagnosis. Eleven of 14 patients had elevated serum LDH. 10 patients (67%) had bone marrow involvement and 12 (80%) had more than one extranodal sites involved. Thirteen patients (87%) had advanced stage disease (stages III and IV). Most patients (93%) had high intermediate or high risk based on the International Prognostic Index (IPI). By immunostain, MYC was expressed in 12/13 (92%) cases, BCL2 in 9/15 (60%) cases, and MYC and BCL2 were coexpressed in 7/13 (54%) cases. All the above clinicopathologic features were similar between SHL and DHL patients (Table 1, p> 0.05), with the only exception of more prevalent BCL2 expression in DHL patients (p=0.01). All 15 SHL patients received chemotherapy: 2 (13%) received R-CHOP, 2 (13%) received R-Hyper CVAD/Ara-C/MTX, 7 (47%) received R-EPOCH and 4 (27%) received other aggressive regimens. One patient also received stem cell transplant (SCT). Twenty one of the 24 DHL patients had treatment information available and there was no statistically significant difference between the two groups (p=0.25). At a median follow up of 16 months, the median overall survival was 10.4 months for SHL, which was not significantly different from that of DHL (19.9 months; p=0.10; Figure 1). Conclusion Our data suggests that clinicopathologic features of MYC SHL is similar to DHL, including the MYC/BCL2 protein coexpression by immunohistochemistry. Despite similar treatment approach in both groups, the response to treatment and prognosis of patients with MYC SHL is similar to those with DHL. Therefore, both MYC SHL and MYC/BCL2 DHL need to be approached similarly while implementing therapeutic decisions. Novel inhibitors in combination with multi-agent chemotherapy to improve prognosis are urgently needed in this subgroup of lymphoma. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
29. Role Of Aggressive Chemotherapeutic Regimens In Double Hit Lymphoma- Can Alternate Aggressive Induction Regimens Overcome The Poor Prognosis Of Diffuse Large B Cell Lymphoma?
- Author
-
David S. Morgan, Judy P. Tsai, John P. Greer, Nishitha Reddy, and Shaoying Li
- Subjects
medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Surgery ,Lymphoma ,International Prognostic Index ,Median follow-up ,Internal medicine ,medicine ,Cytarabine ,Progression-free survival ,business ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
Background Double-hit (DH) diffuse large B cell lymphomas (DLBCL), characterized by concurrent translocations involving MYC and BCL2, or BCL6, portend to have an aggressive clinical course. Recent studies have highlighted the fact that DH lymphomas are resistant to standard R-CHOP or experience a short disease free interval. There is however limited data evaluating patient outcomes with alternative therapy that include aggressive regimens often used to treat high grade lymphoma. Methods Five hundred sixty patients (pts) diagnosed with DLBCL at a single institution between January 2004 and December 2012 were included in our analysis after obtaining IRB approval. Descriptive statistics, Wilcoxon signed rank sum test and Kaplan-Meier analysis were performed using SPSS.19 software. Results Of the 560 pts, 34 were confirmed as DH based on FISH analysis. The median age at diagnosis was 63 yrs (range 36-87). Twenty pts (59%) were male. Thirty-one pts (91%) were Caucasian. Fourteen pts (53%) had an Eastern Cooperative Oncology Group performance status of 2-3. Thirty pts (89%) had advanced stage disease (stages III and IV). Thirteen pts (38%) had bone marrow involvement, and twenty-six pts (76%) had more than one extranodal site. The majority of pts (70%) had high intermediate or high risk based on the International Prognostic Index (IPI). Of the 34 pts, 15 (46%) received R-CHOP, 6 (18%) received R-Hyper CVAD/Ara-C/MTX, 8 (24%) received DA-R-EPOCH and 2 (6%) received other aggressive forms of chemotherapy. Two pts died before any therapy was initiated. Ten pts (29%) received central nervous system prophylaxis. Five pts (15%) underwent stem cell transplant, 2 of which in CR1. Twenty-eight pts (82%) were alive at the time of analysis. At a median follow up of one year, the median overall survival (OS) of all pts was 12.2 months. The median OS was 16.8 months for pts who received R-CHOP and 12.2 months for pts receiving other aggressive chemotherapy (P=0.07) (figure 1). The progression free survival for pts who received R-CHOP was 32.6 months as compared with 7.6 months in pts treated with R-hyper CVAD/Ara-C/MTX or DA-R-EPOCH. This was not statistically significant (P=0.44) (figure 2). In addition, there was no significant difference in disease free interval between the two groups of patients. Conclusion Our data suggests that prognosis of patients with DH-DLBCL remains poor independently of the chemotherapy administered, whether conventional R-CHOP or more aggressive regimens such as R-HyperCVAD or DA-R-EPOCH. Durable long term remission with R-CHOP is still possible in a minority of patients. There is a need to modify and incorporate novel agents in the initial treatment strategy for DH-DLBCL. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.