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Items: 14

1.
Am J Hematol. 2014 Sep;89(9):865-7. doi: 10.1002/ajh.23760. Epub 2014 Jun 19.

The utility of restaging bone marrow biopsy in PET-negative patients with diffuse large B-cell lymphoma and baseline bone marrow involvement.

Author information

1
Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

Abstract

Patients with diffuse large B-cell lymphoma (DLBCL) and pre-treatment bone marrow (BM) involvement require a restaging BM biopsy to document complete remission (CR). We investigated whether BM assessment by restaging PET-CT could obviate the need for a repeat BM biopsy. Patients with DLBCL and a positive BM biopsy at diagnosis were identified from the Mayo Clinic Lymphoma Data Base. The concordance of BM status on restaging histopathology and PET-CT reports and the positive (PPV) and negative predictive value (NPV) of PET-CT were determined. One thousand eighty patients with DLBCL were evaluated and 69 patients (6%) had DLBCL involving the BM at diagnosis. Of 46 patients who completed frontline chemoimmunotherapy, 34 had a restaging PET-CT and BM biopsy and were included in the analysis. Thirty-three patients had a negative BM by both PET-CT and BM biopsy; one patient had persistent BM involvement by biopsy and PET-CT. Thus, restaging PET-CT had 100% PPV and 100% NPV for assessing residual BM disease. The findings were validated in a prospective cohort of 68 DLBCL patients treated on a phase II clinical trial where four patients (6%) had DLBCL involving the BM at diagnosis. All had a negative BM by both restaging BM biopsy and PET-CT. Compared with the gold standard of BM biopsy, PET-CT had a 100% NPV to exclude residual BM disease after frontline therapy. If further validated, DLBCL practice guidelines and response criteria could be modified so that BM biopsy is no longer required to document CR if the restaging PET-CT is negative.

PMID:
24823914
DOI:
10.1002/ajh.23760
[Indexed for MEDLINE]
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3.
Blood. 2014 Mar 20;123(12):1957-60. doi: 10.1182/blood-2014-01-547869.

Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity.

Author information

1
Division of Oncology, Department of Medicine, Stanford University Cancer Institute, Stanford, CA.
PMID:
24652965
PMCID:
PMC3962169
DOI:
10.1182/blood-2014-01-547869
[Indexed for MEDLINE]
Free PMC Article
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4.
Br J Haematol. 2014 Aug;166(3):326-35. doi: 10.1111/bjh.12941. Epub 2014 May 12.

Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment.

Author information

1
Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK; Ernest and Helen Scott Haematology Research Institute, University of Leicester, Leicester, UK.

Abstract

Follicular helper T-cells (Tfh cells) are a subset of CD4(+) T-cells that are essential for normal production of high affinity antibodies. Tfh cells characteristically produce IL21 and IL4 and show high expression of surface markers CXCR5, ICOS, PDCD1 (PD-1) and the chemokine CXCL13. In this review we will focus on the emerging links between Tfh cells and subtypes of T-cell non-Hodgkin lymphoma: angioimmunoblastic T-cell lymphoma (AITL) and ~20% of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) have surface marker features of Tfh cells and share a spectrum of genetic abnormalities. The recurrent genetic abnormalities associated with AITL include mutations in epigenetic modifiers such as TET2 and DNMT3A and the motility and adhesion gene, RHOA, is mutated in up to 70% of cases. ~20% of PTCL-NOS demonstrate RHOA mutations and have other characteristics suggesting an origin in Tfh cells. The recognition that specific genetic and surface markers are associated with malignant Tfh cells suggests that the next few years will bring major changes in diagnostic and treatment possibilities. For example, antibodies against IL21, PDCD1 and ICOS are already in clinical trials for autoimmune disease or other malignancies and antibodies against CXCL13 are in pre-clinical development.

KEYWORDS:

T-cell lymphoma; immunology; monoclonal antibodies

PMID:
24815671
DOI:
10.1111/bjh.12941
[Indexed for MEDLINE]
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5.
Int J Cancer. 2015 Jan 1;136(1):108-16. doi: 10.1002/ijc.28971. Epub 2014 Jun 5.

Epstein-Barr virus and risk of non-Hodgkin lymphoma in the cancer prevention study-II and a meta-analysis of serologic studies.

Author information

1
Epidemiology Research Program, American Cancer Society, Atlanta, GA.

Abstract

Epstein-Barr virus (EBV) causes rare, malignant lymphomas. The role of EBV in other non-Hodgkin lymphomas (NHLs) remains unclear, but mildly reduced immune function could lead to reactivation of EBV and subsequent NHL. We examined the association between prospectively-collected plasma EBV antibodies and NHL risk in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort and conducted a meta-analysis of our and published results. The CPS-II study included 225 NHL cases and 2:1 matched controls. No associations were observed between EBV serostatus or antibody levels and risk of NHL overall. However, when including only the three most common types of NHL (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma), high compared to low early antigen (EA-D) diffuse and BZLF1-encoded replication activator antibodies were associated with approximately 60% higher risk of NHL. Odds ratios (ORs) for EBV nuclear antigen-1 and viral capsid antigen (VCA)-p18 were elevated but not statistically significant. In the meta-analysis, both EA (summary OR = 1.52, 95% confidence interval (CI): 1.16-2.00) and VCA (summary OR = 1.20, 95% CI: 1.00-1.44) were positively associated with NHL risk. These results suggest EBV may be associated with a wider spectrum of NHL subtypes, but further study is needed to confirm and fully understand these associations.

KEYWORDS:

Epstein-Barr virus; multiplex serology; non-Hodgkin lymphoma; prospective study

PMID:
24831943
DOI:
10.1002/ijc.28971
[Indexed for MEDLINE]
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6.
J Clin Oncol. 2014 Jun 10;32(17):1782-91. doi: 10.1200/JCO.2013.52.2631. Epub 2014 May 12.

Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma: results from a two-stage, phase IB study.

Author information

1
Antonio Salar, Hospital del Mar, Barcelona, Spain; Irit Avivi, Rambam Medical Center, Haifa; Ofer Shpilberg, Tel Aviv University, Tel Aviv, Israel; Beate Bittner, Olivier Catalani, Florence Hourcade-Potelleret, and Pakeeza Sayyed, F. Hoffmann-La Roche, Basel, Switzerland; Reda Bouabdallah, Institut Paoli-Calmettes, Marseille, France; Mike Brewster and Christine McIntyre, Roche Products, Welwyn Garden City; George Follows, Addenbrooke's Hospital, University of Cambridge, Cambridge; Andrew Haynes, Nottingham City Hospital, Nottingham, United Kingdom; Andrea Janikova, University Hospital Brno, Brno, Czech Republic; Jean-François Larouche, Hôpital de l'Enfant-Jésus, Centre Hospitalier Universitaire de Québec, Québec, Canada; Michael Pedersen, Herlev Hospital, Herlev, Denmark; Juliana Pereira, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Gayane Tumyan, Russian Cancer Research Center, Moscow, Russia. 94131@parcdesalutmar.cat.
2
Antonio Salar, Hospital del Mar, Barcelona, Spain; Irit Avivi, Rambam Medical Center, Haifa; Ofer Shpilberg, Tel Aviv University, Tel Aviv, Israel; Beate Bittner, Olivier Catalani, Florence Hourcade-Potelleret, and Pakeeza Sayyed, F. Hoffmann-La Roche, Basel, Switzerland; Reda Bouabdallah, Institut Paoli-Calmettes, Marseille, France; Mike Brewster and Christine McIntyre, Roche Products, Welwyn Garden City; George Follows, Addenbrooke's Hospital, University of Cambridge, Cambridge; Andrew Haynes, Nottingham City Hospital, Nottingham, United Kingdom; Andrea Janikova, University Hospital Brno, Brno, Czech Republic; Jean-François Larouche, Hôpital de l'Enfant-Jésus, Centre Hospitalier Universitaire de Québec, Québec, Canada; Michael Pedersen, Herlev Hospital, Herlev, Denmark; Juliana Pereira, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Gayane Tumyan, Russian Cancer Research Center, Moscow, Russia.

Abstract

PURPOSE:

This two-stage phase IB study investigated the pharmacokinetics and safety of subcutaneous (SC) versus intravenous (IV) administration of rituximab as maintenance therapy in follicular lymphoma.

PATIENTS AND METHODS:

In stage 1 (dose finding), 124 patients who responded to rituximab induction were randomly assigned to SC rituximab (375 mg/m2, 625 mg/m2, or an additional group at 800 mg/m2) or IV rituximab (375 mg/m2). The objective was to determine an SC dose that would yield a rituximab serum trough concentration (Ctrough) in the same range as that of IV rituximab. In stage 2, 154 additional patients were randomly assigned (1:1) to SC rituximab (1,400 mg) or IV rituximab (375 mg/m2) given at 2- or 3-month intervals. The objective was to demonstrate noninferior rituximab Ctrough of SC rituximab relative to IV rituximab 375 mg/m2.

RESULTS:

Stage 1 data predicted that a fixed dose of 1,400 mg SC rituximab would result in a serum Ctrough in the range of that of IV rituximab. Noninferiority (ie, meeting the prespecified 90% CI lower limit of 0.8) was then confirmed in stage 2, with geometric mean Ctrough SC:Ctrough IV ratios for the 2- and 3-month regimens of 1.24 (90% CI, 1.02 to 1.51) and 1.12 (90% CI, 0.86 to 1.45), respectively. Overall safety profiles were similar between formulations (in stage 2, 79% of patients experienced one or more adverse events in each group). Local administration-related reactions (mainly mild to moderate) occurred more frequently after SC administration.

CONCLUSION:

The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior Ctrough levels relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00930514.

PMID:
24821885
DOI:
10.1200/JCO.2013.52.2631
[Indexed for MEDLINE]
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7.
J Immunol. 2014 Jun 15;192(12):5852-62. doi: 10.4049/jimmunol.1302068. Epub 2014 May 14.

Exosomes derived from Burkitt's lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells.

Author information

1
Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 17177 Stockholm, Sweden; cindy.gutzeit@mssm.edu.
2
Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
3
Institut Hospital del la Mar d'Investigacions Mèdiques, 08003 Barcelona, Spain; and.
4
Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 17177 Stockholm, Sweden.
5
Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 17177 Stockholm, Sweden;

Abstract

Exosomes, nano-sized membrane vesicles, are released by various cells and are found in many human body fluids. They are active players in intercellular communication and have immune-suppressive, immune-regulatory, and immune-stimulatory functions. EBV is a ubiquitous human herpesvirus that is associated with various lymphoid and epithelial malignancies. EBV infection of B cells in vitro induces the release of exosomes that harbor the viral latent membrane protein 1 (LMP1). LMP1 per se mimics CD40 signaling and induces proliferation of B lymphocytes and T cell-independent class-switch recombination. Constitutive LMP1 signaling within B cells is blunted through the shedding of LMP1 via exosomes. In this study, we investigated the functional effect of exosomes derived from the DG75 Burkitt's lymphoma cell line and its sublines (LMP1 transfected and EBV infected), with the hypothesis that they might mimic exosomes released during EBV-associated diseases. We show that exosomes released during primary EBV infection of B cells harbored LMP1, and similar levels were detected in exosomes from LMP1-transfected DG75 cells. DG75 exosomes efficiently bound to human B cells within PBMCs and were internalized by isolated B cells. In turn, this led to proliferation, induction of activation-induced cytidine deaminase, and the production of circle and germline transcripts for IgG1 in B cells. Finally, exosomes harboring LMP1 enhanced proliferation and drove B cell differentiation toward a plasmablast-like phenotype. In conclusion, our results suggest that exosomes released from EBV-infected B cells have a stimulatory capacity and interfere with the fate of human B cells.

PMID:
24829410
PMCID:
PMC4174405
DOI:
10.4049/jimmunol.1302068
[Indexed for MEDLINE]
Free PMC Article
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10.
Leuk Lymphoma. 2015 Feb;56(2):383-9. doi: 10.3109/10428194.2014.921296. Epub 2014 Jul 17.

Intensive chemotherapy and consolidation with high dose therapy and autologous stem cell transplant in patients with mantle cell lymphoma.

Author information

1
Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine , Atlanta, GA , USA.

Abstract

Mantle cell lymphoma (MCL) remains incurable with conventional chemotherapy without consensus on the optimal initial treatment. We examined our single center experience with frontline therapy for patients with MCL in consecutive cases diagnosed 1995-2011. Among 81 patients, median age was 59 (28% were ≥65 years of age), 95% had stage III/IV disease and 54% had a low risk MCL International Prognostic Index score. Thirty-five percent (n=28) received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and 65% received R-HCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate/cytarabine; n=53). Forty-one patients were consolidated with autologous stem cell transplant (ASCT). There were no significant differences in 2-year survival for R-CHOP versus R-HCVAD (p=0.10) or for ASCT versus observation (p=0.06). After controlling for clinical factors, R-HCVAD followed by ASCT was associated with superior progression-free survival (hazard ratio 0.26, 95% confidence interval 0.09-0.75).

KEYWORDS:

Mantle cell lymphoma; R-CHOP regimen; R-HCVAD regimen; autologous transplant; outcomes

PMID:
24828864
DOI:
10.3109/10428194.2014.921296
[Indexed for MEDLINE]
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11.
Leuk Lymphoma. 2015 Feb;56(2):420-5. doi: 10.3109/10428194.2014.924123. Epub 2014 Aug 4.

MYD88 mutant lymphoplasmacytic lymphoma/Waldenström macroglobulinemia has distinct clinical and pathological features as compared to its mutation negative counterpart.

Author information

1
Hematopathology Laboratory, Tata Memorial Centre , Mumbai , India.

Abstract

In a first series from India, we report 32 cases of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) over 7 years. Here, we analyzed 32 patients with LPL/WM for MYD88 L265P mutation and correlated mutation staus with hematological and biochemical parameters and also with the International Prognostic Scoring System (ISSWM) and treatment response. Twenty-seven out of 32 cases of LPL/WM (84.3%) harbored the MYD88 L265P mutation. MYD88 wild-type WM was associated with a lower number of tumor cells (p<0.01) and older age (p=0.02) and a lower ISSWM score at presentation (p=0.03) as compared to mutated LPL/WM. On evaluation of response (n=23), 44.4% of patients with MYD88 mutated LPL/WM had progressive disease, whereas no patient in the MYD88 unmutated group changed their baseline status. We confirm the high frequency of MYD88 mutations in LPL/WM. Although the number of MYD88 wild-type cases was limited, our data indicate that MYD88 may represent an adverse prognostic marker for LPL/WM.

KEYWORDS:

ISSWM; India; Lymphoplasmacytic lymphoma; MYD88 mutation; Waldenström; macroglobulinemia

PMID:
24828863
DOI:
10.3109/10428194.2014.924123
[Indexed for MEDLINE]
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13.
Leuk Lymphoma. 2015 Feb;56(2):293-300. doi: 10.3109/10428194.2014.910660. Epub 2014 Jun 16.

Relapsed/refractory diffuse large B-cell lymphoma: review of the management of transplant-eligible patients.

Author information

1
Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Center, Cleveland Clinic , Cleveland, OH , USA.

Abstract

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is difficult to treat, with limited therapeutic options. Review of prognostic indices, DLBCL genetic classification, previous rituximab exposure, interval from previous therapy, chemosensitivity to salvage therapy and response on imaging is helpful when deciding upon appropriate candidates for further therapy. For appropriately selected patients, the primary strategy is to obtain remission with salvage therapy and proceed to autologous stem cell transplant (ASCT). However, salvage therapy and transplant conditioning regimens are suboptimal, as are therapeutic options for patients who relapse following ASCT. Recent research highlights the ongoing difficulty in the treatment of relapsed/refractory DLBCL, and novel treatments are needed.

KEYWORDS:

DLBCL; Lymphoma; management; refractory; relapse

PMID:
24813764
DOI:
10.3109/10428194.2014.910660
[Indexed for MEDLINE]
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14.
Oncogene. 2015 Apr 2;34(14):1843-52. doi: 10.1038/onc.2014.112. Epub 2014 May 12.

Anaplastic large cell lymphoma-propagating cells are detectable by side population analysis and possess an expression profile reflective of a primitive origin.

Author information

1
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
2
Molecular Diagnostics and Personalised Therapeutics Unit, College of Applied Medical Sciences, University of Ha'il, Ha'il, Kingdom of Saudi Arabia.
3
Department of Histopathology and Cytology, Addenbrooke's Hospital, Cambridge, UK.
4
Department of Paediatric Oncology, Addenbrooke's Hospital, Cambridge, UK.
5
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
6
1] Department for Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Im Neuenheimer Feld, Heidelberg, Germany [2] European Research Initiative on ALK related malignancies (ERIA).
7
1] European Research Initiative on ALK related malignancies (ERIA) [2] Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria [3] Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
8
1] Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
9
1] Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK [2] European Research Initiative on ALK related malignancies (ERIA).

Abstract

Cancer stem cells or tumour-propagating cells (TPCs) have been identified for a number of cancers, but data pertaining to their existence in lymphoma so far remain elusive. We show for the first time that a small subset of cells purified from human anaplastic lymphoma kinase (ALK)-positive and -negative, anaplastic large cell lymphoma cell lines and primary patient tumours using the side population (SP) technique have serial tumour-propagating capacity both in vitro and in vivo; they give rise to both themselves and the bulk tumour population as well as supporting growth of the latter through the production of soluble factors. In vivo serial dilution assays utilising a variety of model systems inclusive of human cell lines, primary human tumours and nucleophosmin (NPM)-ALK-induced murine tumours demonstrate the TPC frequency to vary from as many as 1/54 to 1/1336 tumour cells. In addition, the SP cells express higher levels of pluripotency-associated transcription factors and are enriched for a gene expression profile consistent with early thymic progenitors. Finally, our data show that the SP cells express higher levels of the NPM-ALK oncogene and are sensitive to an ALK inhibitor.

PMID:
24814516
DOI:
10.1038/onc.2014.112
[Indexed for MEDLINE]
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