- Email: [email protected]
Long-Term Remissions of Patients With Follicular Lymphoma Grade 3 Treated With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP)
Abstracts DLBCL patients from developed countries who were treated with R-CHOP. Design: A cohort (n¼732) of patients with DLBCL treated with R-CHOP chemotherapy are included in the International DLBCL Rituximab-CHOP Consortium Program. All cases were diagnosed according to the WHO criteria. DLBCLs transformed from a low-grade B-cell lymphoma or associated with acquired immunodeficiency (e.g. human immunodeficiency virus infection), primary cutaneous DLBCLs, primary central nervous system DLBCLs, and primary mediastinal large B-cell lymphomas were excluded. For the study group we collected clinical data and assessed different biomarkers by immunohistochemistry. We also assessed for genetic abnormalities by fluorescent in situ hybridization, performed mutation analysis, gene expression profiling (GEP) and gene set enrichment analysis (GSEA). Presence of EBV was assessed by in situ hybridization for EBV encoded RNA (EBER). Setting: This study can aid lymphoma specialists in improving risk stratification of DLBCL patients. Results: Twenty-eight (4.0%) patients were positive for EBV with a median age of 60.5 years (add range). No clinical characteristics distinguished patients with EBV+ DLBCL from patients with EBV-negative DLBCL. Genetic aberrations were rarely seen in EBV+ DLBCL. NF-kB p50, phosphoSTAT-3 and CD30 were more commonly expressed in EBV+ DLBCL (P<.05). Significant differences in survival were not observed in patients with EBV+ DLBCL versus EBV-negative DLBCL. CD30 co-expression appeared to confer inferior outcome although statistical significance was not achieved. GEP showed a unique expression signature in EBV+ DLBCL and GSEA revealed enhanced activity of the NF-kB and JAK/STAT pathways. Conclusions: The clinical characteristics of patients with EBV+ DLBCL versus EBV-negative DLBCL are similar. EBV infection per se does not predict a worse outcome. CD30 expression is more common in EBV+ DLBCL and, when present, is associated with an adverse outcome. EBV+ DLBCL has a unique genetic signature.
(Mod Pathol 2013; 26(S2); Abstract #1489). Bortezomib interferes with the NFkB pathway via inhibition of the 26S proteosome. This prevents the nuclear translocation of p-NFkBp65 (Ser536) resulting in the inhibition of transcriptional activation of prosurvival pathways and stabilization of proapoptotic proteins. It also inhibits mTORC2, an upstream activator of the AKT prosurvival pathway. A Phase II study using CHOP-bortezomib (CHOP-B) in T-cell lymphomas showed up to 87% response rate and 73% complete remissions (Kim, SJ: Eur J Cancer. 2012 48(17):3223). Despite favorable clinical results, they were unable to show NFkB pathway activation using a non-phosphorylated NFkB antibody. However, a significant number of patients experienced cell mediated opportunistic infections commonly associated with inhibition of the NFkB pathway. Case Report: A 70-year-old woman was diagnosed on 7/ 25/2012 with a peripheral T-cell lymphoma angioimmunoblastic subtype, stage IVB. She presented with progressive bilateral bulky cervical lymphadenopathy, fever and weight loss. Considering the existing clinical data and our previous study’s findings, she was treated with CHOP eB. After the first cycle of treatment cycle of treatment she was essentially in complete clinical and radiological remission, receiving a total of five courses of treatment. (CT PET scans done at baseline, 2 and 8 months of treatment). Treatment was well tolerated, with significant performance status improvement. A morphoproteomic analysis of her tumor revealed high expression of p-NF-kBp65 (Ser 536) and p-mTOR (Ser2448), consistent with the results of our previous study. Conclusions: A greater understanding of the molecular pathways involved in T-cell lymphomas may result in identification of potential therapeutic targets which could improve the overall prognosis of these malignancies. Preliminary clinical results, together with our immunohistochemical data, provide support for further exploration of targeted inhibition of NF-kB and mTORC in the treatment of PTCLs.
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509
Expression of NFkB/mTORC Pathway Proteins is Associated With Response to CHOP plus Bortezomib (CHOP-B) in a Patient With Angioimmunoblastic Peripheral T-cell Lymphoma (AI-PTCL)
Long-Term Remissions of Patients With Follicular Lymphoma Grade 3 Treated With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP)
1 Department of Pathology and Laboratory Medicine, the University of Texas at Houston; 2Department of Internal Medicine, Division of
Paolo Strati, Jorge E. Romaguera, Larry W. Kwak, Fredrick B. Hagemeister, Alma Rodriguez, Yasuhiro Oki, Jason Westin, Francesco Turturro, Michael J. Overman, Sattva S. Neelapu, Nathan Fowler, Luis Fayad
Oncology, the University of Texas at Houston
The University of Texas MD Anderson Cancer Center, Houston, Texas
Background: Increasing knowledge of T cell lymphomas’ biology has identified relevant molecular pathways implicated in the biology of this heterogeneous group of diseases. The immunohistochemical characterization of these pathways provides surrogate markers of biological activity and potential therapeutic targets. Utilizing a morphoproteomic analysis, we found a high expression of NFkB and mTORC proteins in ten cases of T-cell lymphomas
Background: Follicular lymphoma grade 3 (FLG3) are recognized as a distinct entity in the World Health Organization classification of lymphoma. Their natural history is similar to that of diffuse large B cell lymphomas and there is still debate about their optimal management. Methods: We conducted a retroprospective analysis of 156 patients with FLG3 receiving frontline treatment at MD Anderson Cancer Center between 06/1973 and 11/2004.
Andres E. Quesada,1 Adan Rios,2 Robert E. Brown,1 Nghia D. Nguyen1
Clinical Lymphoma, Myeloma & Leukemia September 2014
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Abstracts PATIENTS CHARACTERISTICS (N[45)
NUMBER (%)
AGE > 60 years
21 (47)
MALES ECOG 1-2
23 (51) 1 (2)
HISTOLOGY 3B STAGE 3-4
40 (89) 36 (80)
NODAL SITES > 4 BULKY DISEASE (> 6 cm)
17 (38) 5 (11)
EXTRANODAL SITES > 1 BONE MARROW INVOLVEMENT
6 (13) 14 (31)
B SYMPTOMS IPI 3-4
5 (11) 8 (18)
FLIPI 3-5 HEMOGLOBIN < 12 g/dL
15 (33) 8 (18)
LDH > 618 IU/L BETA-2-MICROGLOBULIN > 4 mg/L
11 (24) 8 (18)
analysis, the only factor associated with a shorter OS after relapse was transformation (p¼0.01). Baseline characteristics associated with transformation on MVA were IPI score 3-4 (OR 1.1, p¼0.004) and elevated LDH (OR 2.4, p¼0.01). Nine patients died, 2 (22%) of lymphoma progression, 4 (44%) of therapy-related acute myeloid leukemia (AML) and 3 (32%) of cancer-unrelated causes. On MVA, factors associated with shorter OS after R-CHOP were age > 60 years (HR 11, p¼0.02) and LDH > 618 IU/L (HR 5.9, p¼0.01). On univariate analysis, age > 60 years was the only factor associated with AML onset (p¼0.04). Conclusions: RCHOP is an effective treatment for patients with FLG3 and small number of nodal sites, with rare late progressions. The incidence of transformation is low but is fatal. Onset of second myeloid malignancies is the main cause of death and warrants caution in elderly patients.
510 Phenotypic and Genotypic Profiling of MDM2, Respective to the TP53 Genetic Status, in Diffuse Large Bcell Lymphoma Patients Treated With Rituximab-CHOP Immunochemotherapy: A Report from the International DLBCL Rituximab-CHOP Consortium Program Zijun Y. Xu-Monette,1 Michael B. Møller,2 Alexander Tzankov,3 Santiago Montes-Moreno,4 Wenwei Hu,5 Ganiraju C. Manyam,6 Louise Kristensen,2 Lei Fan,7 Carlo Visco,8 Karen Dybkær,9 April Chiu,10 Wayne Tam,11 Youli Zu,12 Govind Bhagat,13 Kristy L. Richards,14 Eric D. Hsi,15 William W.L. Choi,16 J. Han van Krieken,17 Qin Huang,18 Jooryung Huh,19 Weiyun Ai,20 Maurilio Ponzoni,21 Andrés J.M. Ferreri,21 Lin Wu,22 Xiaoying Zhao,23 Carlos E. Bueso-Ramos,1 Sa A. Wang,1 Ronald S. Go,24 Yong Li,25 Jane N. Winter,26 Miguel A. Piris,4 L. Jeffrey Medeiros,1 Ken H. Young1 1
Department of Hematopathology, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA; 2Odense University Hospital, Odense, Denmark; 3University Hospital, Basel, Switzerland;
Multivariate analysis (MVA) was performed using Hazard Ratio (HR) Cox regression or logistic regression with odds ratio (OR). Results: Patient baseline characteristics are shown in the Table. Forty-five (29%) patients received R-CHOP, of which 12 (27%) received more than 6 cycles and 9 (20%) and radiation therapy as consolidation. The overall response rate was 100% and the complete remission (CR) rate was 96%. After a median follow-up of 9 (2-12) years, median PFS has not been reached. Nearly all 14 (31%) relapses occurred within 3 years (Figure). On MVA, the only characteristic associated with a shorter PFS was the presence of > 4 nodal sites (HR 4.2, p¼0.03). Among relapsed patients, 3 (21%) transformed to DLBCL and died. Median OS has not been reached for all R-CHOP treated and relapsed patients. On univariate
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Clinical Lymphoma, Myeloma & Leukemia September 2014
4
Hospital Universitario Marques de Valdecilla, Santander, Spain;
5
Rutgers Cancer Institute of New Jersey, Rutgers the State University
of New Jersey, New Brunswick, NJ, USA; 6Department of Biostatistics and Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China; 8San Bortolo Hospital, Vicenza, Italy; 9Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; Center, New York, NY, USA; versity, New York, NY, USA; USA;
10
Memorial Sloan-Kettering Cancer
11
Weill Medical College of Cornell Uni-
12
The Methodist Hospital, Houston, TX,
13
Columbia University Medical Center and New York Presby-
terian Hospital, New York, NY, USA;
14
University of North Carolina
School of Medicine, Chapel Hill, NC, USA;
15
Cleveland Clinic,
(Mod Pathol 2013; 26(S2); Abstract #1489). Bortezomib interferes with the NFkB pathway via inhibition of the 26S proteosome. This prevents the nuclear translocation of p-NFkBp65 (Ser536) resulting in the inhibition of transcriptional activation of prosurvival pathways and stabilization of proapoptotic proteins. It also inhibits mTORC2, an upstream activator of the AKT prosurvival pathway. A Phase II study using CHOP-bortezomib (CHOP-B) in T-cell lymphomas showed up to 87% response rate and 73% complete remissions (Kim, SJ: Eur J Cancer. 2012 48(17):3223). Despite favorable clinical results, they were unable to show NFkB pathway activation using a non-phosphorylated NFkB antibody. However, a significant number of patients experienced cell mediated opportunistic infections commonly associated with inhibition of the NFkB pathway. Case Report: A 70-year-old woman was diagnosed on 7/ 25/2012 with a peripheral T-cell lymphoma angioimmunoblastic subtype, stage IVB. She presented with progressive bilateral bulky cervical lymphadenopathy, fever and weight loss. Considering the existing clinical data and our previous study’s findings, she was treated with CHOP eB. After the first cycle of treatment cycle of treatment she was essentially in complete clinical and radiological remission, receiving a total of five courses of treatment. (CT PET scans done at baseline, 2 and 8 months of treatment). Treatment was well tolerated, with significant performance status improvement. A morphoproteomic analysis of her tumor revealed high expression of p-NF-kBp65 (Ser 536) and p-mTOR (Ser2448), consistent with the results of our previous study. Conclusions: A greater understanding of the molecular pathways involved in T-cell lymphomas may result in identification of potential therapeutic targets which could improve the overall prognosis of these malignancies. Preliminary clinical results, together with our immunohistochemical data, provide support for further exploration of targeted inhibition of NF-kB and mTORC in the treatment of PTCLs.
508
509
Expression of NFkB/mTORC Pathway Proteins is Associated With Response to CHOP plus Bortezomib (CHOP-B) in a Patient With Angioimmunoblastic Peripheral T-cell Lymphoma (AI-PTCL)
Long-Term Remissions of Patients With Follicular Lymphoma Grade 3 Treated With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP)
1 Department of Pathology and Laboratory Medicine, the University of Texas at Houston; 2Department of Internal Medicine, Division of
Paolo Strati, Jorge E. Romaguera, Larry W. Kwak, Fredrick B. Hagemeister, Alma Rodriguez, Yasuhiro Oki, Jason Westin, Francesco Turturro, Michael J. Overman, Sattva S. Neelapu, Nathan Fowler, Luis Fayad
Oncology, the University of Texas at Houston
The University of Texas MD Anderson Cancer Center, Houston, Texas
Background: Increasing knowledge of T cell lymphomas’ biology has identified relevant molecular pathways implicated in the biology of this heterogeneous group of diseases. The immunohistochemical characterization of these pathways provides surrogate markers of biological activity and potential therapeutic targets. Utilizing a morphoproteomic analysis, we found a high expression of NFkB and mTORC proteins in ten cases of T-cell lymphomas
Background: Follicular lymphoma grade 3 (FLG3) are recognized as a distinct entity in the World Health Organization classification of lymphoma. Their natural history is similar to that of diffuse large B cell lymphomas and there is still debate about their optimal management. Methods: We conducted a retroprospective analysis of 156 patients with FLG3 receiving frontline treatment at MD Anderson Cancer Center between 06/1973 and 11/2004.
Andres E. Quesada,1 Adan Rios,2 Robert E. Brown,1 Nghia D. Nguyen1
Clinical Lymphoma, Myeloma & Leukemia September 2014
- S145
Abstracts PATIENTS CHARACTERISTICS (N[45)
NUMBER (%)
AGE > 60 years
21 (47)
MALES ECOG 1-2
23 (51) 1 (2)
HISTOLOGY 3B STAGE 3-4
40 (89) 36 (80)
NODAL SITES > 4 BULKY DISEASE (> 6 cm)
17 (38) 5 (11)
EXTRANODAL SITES > 1 BONE MARROW INVOLVEMENT
6 (13) 14 (31)
B SYMPTOMS IPI 3-4
5 (11) 8 (18)
FLIPI 3-5 HEMOGLOBIN < 12 g/dL
15 (33) 8 (18)
LDH > 618 IU/L BETA-2-MICROGLOBULIN > 4 mg/L
11 (24) 8 (18)
analysis, the only factor associated with a shorter OS after relapse was transformation (p¼0.01). Baseline characteristics associated with transformation on MVA were IPI score 3-4 (OR 1.1, p¼0.004) and elevated LDH (OR 2.4, p¼0.01). Nine patients died, 2 (22%) of lymphoma progression, 4 (44%) of therapy-related acute myeloid leukemia (AML) and 3 (32%) of cancer-unrelated causes. On MVA, factors associated with shorter OS after R-CHOP were age > 60 years (HR 11, p¼0.02) and LDH > 618 IU/L (HR 5.9, p¼0.01). On univariate analysis, age > 60 years was the only factor associated with AML onset (p¼0.04). Conclusions: RCHOP is an effective treatment for patients with FLG3 and small number of nodal sites, with rare late progressions. The incidence of transformation is low but is fatal. Onset of second myeloid malignancies is the main cause of death and warrants caution in elderly patients.
510 Phenotypic and Genotypic Profiling of MDM2, Respective to the TP53 Genetic Status, in Diffuse Large Bcell Lymphoma Patients Treated With Rituximab-CHOP Immunochemotherapy: A Report from the International DLBCL Rituximab-CHOP Consortium Program Zijun Y. Xu-Monette,1 Michael B. Møller,2 Alexander Tzankov,3 Santiago Montes-Moreno,4 Wenwei Hu,5 Ganiraju C. Manyam,6 Louise Kristensen,2 Lei Fan,7 Carlo Visco,8 Karen Dybkær,9 April Chiu,10 Wayne Tam,11 Youli Zu,12 Govind Bhagat,13 Kristy L. Richards,14 Eric D. Hsi,15 William W.L. Choi,16 J. Han van Krieken,17 Qin Huang,18 Jooryung Huh,19 Weiyun Ai,20 Maurilio Ponzoni,21 Andrés J.M. Ferreri,21 Lin Wu,22 Xiaoying Zhao,23 Carlos E. Bueso-Ramos,1 Sa A. Wang,1 Ronald S. Go,24 Yong Li,25 Jane N. Winter,26 Miguel A. Piris,4 L. Jeffrey Medeiros,1 Ken H. Young1 1
Department of Hematopathology, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA; 2Odense University Hospital, Odense, Denmark; 3University Hospital, Basel, Switzerland;
Multivariate analysis (MVA) was performed using Hazard Ratio (HR) Cox regression or logistic regression with odds ratio (OR). Results: Patient baseline characteristics are shown in the Table. Forty-five (29%) patients received R-CHOP, of which 12 (27%) received more than 6 cycles and 9 (20%) and radiation therapy as consolidation. The overall response rate was 100% and the complete remission (CR) rate was 96%. After a median follow-up of 9 (2-12) years, median PFS has not been reached. Nearly all 14 (31%) relapses occurred within 3 years (Figure). On MVA, the only characteristic associated with a shorter PFS was the presence of > 4 nodal sites (HR 4.2, p¼0.03). Among relapsed patients, 3 (21%) transformed to DLBCL and died. Median OS has not been reached for all R-CHOP treated and relapsed patients. On univariate
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Clinical Lymphoma, Myeloma & Leukemia September 2014
4
Hospital Universitario Marques de Valdecilla, Santander, Spain;
5
Rutgers Cancer Institute of New Jersey, Rutgers the State University
of New Jersey, New Brunswick, NJ, USA; 6Department of Biostatistics and Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China; 8San Bortolo Hospital, Vicenza, Italy; 9Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; Center, New York, NY, USA; versity, New York, NY, USA; USA;
10
Memorial Sloan-Kettering Cancer
11
Weill Medical College of Cornell Uni-
12
The Methodist Hospital, Houston, TX,
13
Columbia University Medical Center and New York Presby-
terian Hospital, New York, NY, USA;
14
University of North Carolina
School of Medicine, Chapel Hill, NC, USA;
15
Cleveland Clinic,