Are We Ready To Stratify Treatment for Diffuse Large B-Cell Lymphoma Using Molecular Hallmarks?

Oct 2012

Barton S, Hawkes EA, Wotherspoon A, Cunningham D.

Source

Department of Medicine and.

Abstract

The division of the heterogeneous entity of diffuse large B-cell lymphoma (DLBCL) into the ontogenic phenotypes of germinal center B-cell-like (GCB) and activated B-cell-like (ABC) is optimally determined by gene expression profiling (GEP), although simpler immunohistochemistry (IHC) algorithms are alternatively being used. The cell-of-origin (COO) classification assists in prognostication and may be predictive of response to therapy. Mounting data suggests that IHC methods of classifying COO may be inaccurate. GEP categorization of COO is superior in defining prognostically and biologically distinct DLBCL subtypes, but current barriers to its widescale use include inaccessibility, cost, and lack of methodological standardization and prospective validation. The poorer prognosis of ABC-DLBCL is frequently associated with constitutive activity in the NF-κB pathway and aberrations in upstream or downstream regulators of this pathway. The molecular mechanisms underlying lymphomagenesis in GCB-DLBCL are arguably less well defined, but C-REL amplification and mutations in BCL-2 and EZH2 are common. New technologies, such as next-generation sequencing, are rapidly revealing novel pathogenic genetic aberrations, and DLBCL treatment strategies are increasingly being designed focusing on distinctive pathogenic drivers within ontogenic phenotypes. This review examines emerging molecular targets and novel therapeutic agents in DLBCL, and discusses whether stratifying therapy for DLBCL using molecular features is merited by current preclinical and clinical evidence.

The Oncologist

Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20+ Diffuse Large B-Cell Lymphoma: Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma.

Oct 2012

Gisselbrecht C, Schmitz N, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Milpied NJ, Radford J, Ketterer N,Shpilberg O, Dührsen U, Hagberg H, Ma DD, Viardot A, Lowenthal R, Brière J, Salles G, Moskowitz CH, Glass B.

Source

Christian Gisselbrecht and Josette Brière, Hôpital Saint Louis, Paris; Nicolas Mounier, Centre Hospitalier Universitaire de l'Archet, Nice; Noel J. Milpied, Hôpital Haut-Lévêque, Pessac; Gilles Salles, Hospices Civils de Lyon and Université de Lyon, Lyon, France; Norbert Schmitz and Bertram Glass, Asklepios Klinik St Georg, Hamburg; Ulrich Dührsen, Universitätsklinikum Essen, Essen; Andreas Viardot, Universitätsklinik Ulm, Ulm, Germany; Devinder Singh Gill, Princess Alexandra Hospital, Woodville, South Australia; David D. Ma, St Vincent's Hospital Sydney, Darlinghurst, New South Wales; Ray Lowenthal, Royal Hobart Hospital, Tasmania, Australia; David C. Linch, University College London, Cancer Institute, London; John Radford, University of Manchester, Christie Hospital National Health Service Trust, Manchester, United Kingdom; Marek Trneny, Charles University General Hospital, Prague, Czech Republic; Andre Bosly, Université Catholique de Louvain Mont-Godinne, Yvoir, Belgium; Nicolas Ketterer, Clinique Bois-Cerf, Lausanne, Switzerland; Ofer Shpilberg, Davidoff Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Hans Hagberg, Akademiska Sjukhuset, Uppsala, Sweden; and Craig H. Moskowitz, Memorial Sloan-Kettering Cancer Center, New York, NY.

Abstract

PURPOSE

The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. 

PATIENTS AND METHODS

In total, 477 patients with CD20(+) DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. 

RESULTS: 

46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 - EFS: 37% v 61% for saaIPI , - and prior treatment with rituximab - EFS: 47% v 59% for no prior rituximab - . A significant difference in EFS between women at sixty three percent and men at forty six percent was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor , as was male sex. 

CONCLUSION

In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.

Full Text: Journal of Clinical Oncology

CD137 Ligand Is Expressed in Primary and Secondary Lymphoid Follicles and in B-cell Lymphomas: Diagnostic and Therapeutic Implications.

Oct 2012

Zhao S, Zhang H, Xing Y, Natkunam Y.

Source

Departments of *Pathology ‡Surgery, Stanford University School of Medicine, Stanford, CA †Stem Cell Center, Zhengzhou University School of Medicine, Zhengzhou, China.

Abstract

CD137 ligand (4-1BB ligand, TNFSF9, CD137L) is a member of the tumor necrosis factor family whose binding to its receptor, CD137 (4-1BB, TNFRSF9), mediates costimulatory and prosurvival signals necessary for T-cell activation and regulation of humoral immune responses. Recent studies have shown that anti-CD137 immunotherapy has promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. Here, we define the tissue expression profile of CD137L, which has not been previously explored. We characterized the expression of CD137L in normal and neoplastic human hematopoietic and nonhematopoietic tissue and found that CD137L is preferentially expressed in B cells of the primary follicles, mantle zones of the secondary follicles, germinal centers, and in normal endothelial cells. Double immunofluorescence labeling in tissue sections and flow cytometry analysis further showed that CD137L is a potential new marker of memory B cells. Evaluation of over 700 human hematopoietic tumors revealed that the majority of B-celllymphomas expressed CD137L, which include mantle cell lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. In contrast, CD137L expression was lacking in Hodgkin lymphoma and T-cell lymphoma. Our findings suggest that CD137L is a novel diagnostic marker of subtypes of non-Hodgkin B-cell lymphomas and raise the possibility that its expression on tumor cells may be directly targeted for immunomodulatory therapy for lymphoid and other malignancies.

PubMed

Lymphoma and Other Lymphoproliferative Disorders in IBD: A Review.

Oct 2012

Subramaniam K, D'Rozario J, Pavli P.

Source

Gastroenterology and Hepatology Unit, Canberra Hospital, ACT.

Abstract

The lymphoproliferative disorders (LD) are a heterogeneous group of at least 70 conditions that result from the clonal proliferation of B, T and NK cells. IBD-associated lymphomas are typically B-cell LD, while T-cell or Hodgkin's lymphomas are rare. In IBD patients not on immunosuppression, the risk of LD seems to be similar or slightly higher than the background population risk. Thiopurine therapy is associated with an increased risk: the relative risk is increased 4-6 fold and the absolute risk varies between 1 in 4,000-5,000 for those aged 20-29 to 1 in 300-400 in those over 70. It is difficult to quantify the risk of anti-TNF therapy alone, however it appears to be less than for thiopurines alone. There is particular concern regarding: the development of post-transplant-like LD in those with latent EBV infection exposed to immunosuppressives; the occurrence of hepatosplenic T cell lymphoma in patients treated with combination anti-TNF and thiopurine therapy; and the development of hemophagocytic lymphohistiocytosis in those who acquire a primary EBV or other infection whilst on immunosuppressive medication. There are currently no guidelines for monitoring EBV (or other virus) status in patients on immunosuppression, although it could be used to monitor those who have a prior history of lymphoma and are about to start a thiopurine or anti-TNF agent. In discussing the risks of lymphoproliferative disorders associated with agents used for the treatment of IBD, patients can often be reassured that the benefits of such therapy still outweigh the small, but real, risks.

PubMed

The Hans algorithm failed to predict outcome in patients with diffuse large B-cell lymphoma treated with rituximab.

Oct 2012

Benesova K, Forsterova K, Votavova H, Campr V, Stritesky J, Velenska Z, Prochazka B, Pytlik R, Trneny M.

Abstract

Diffuse large B-cell lymphoma (DLBCL) consists of at least two biologically and pathogenetically different subtypes, the germinal centre B-cell (GCB) and the activated B cell type (ABC). It has been suggested that immunohistochemistry can discriminate these subtypes as well. The aim of this study was to verify the validity of the most commonly used Hans algorithm in patients with DLBCL treated with anthracycline- based chemotherapy with rituximab. Immunohistochemical staining using standard protocols was performed on formalin fixed paraffin-embedded tissues. CD20, CD5, CD23, BCL2, CD10, BCL6, MUM1 and Ki67 antibodies were applied. Out of 120 examined cases 52 patients were evaluated as GCB type and 68 patients as having non-GCB, out of a set of 99 patients treated with immunochemotherapy 45 patients with GCB and 54 patients with non-GCB DLBCL were identified. In this set of patients, there was no statistically significant difference neither in overall survival (OS) (HR 1.47 95% CI 0.51-2.63; p=0.45) nor in progression free survival (PFS) (HR 1.57, 95 % CI 0.76-3.22; p=0.731) between both groups. Keywords: DLBCL, Hans, rituximab, GC, nonGC.

DOI System

PubMed

Utility of the PET-CT in the evaluation of early response to treatment in the diffuse large B-cell lymphoma. Preliminary results.

May 2012

[Article in English, Spanish]

Cortés Romera M, Gámez Cenzano C, Caresia Aróztegui AP, Martín-Comín J, González-Barca E, Ricart Brulles Y, Palacios Abufón A, Robles Barba J, Rodríguez-Bel L, Rossi Seoane S, Fernández de Sevilla A.

Source

Unitat PET, Institut de Diagnòstic per la Imatge (IDI), Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, España.

Abstract

OBJECTIVE:

To assess the role of FDG-PET/CT performed after the first cycles of chemotherapy in the prediction of response to treatment in patients with diffuse large B-cell lymphoma.

METHODS:

Twenty patients (mean age: 48 years) were included, 16 initial staging and 4 relapse. All patients underwent PET/CT at 3 times: 1) Baseline, 2) After 1-3 cycles of chemotherapy (early response assessment), and 3) End of treatment (evaluation of final response). Early PET/CT findings were correlated to the end-treatment PET/CT and follow-up. The evaluation of the response was established according to the decrease in uptake of the lesions (SUVmax). In the early assessment, a good response indicator (GRI) was obtained when the lesion disappeared or had more than 50% reduction in SUVmax. At the end of the treatment, a complete metabolic response (CMR) was determined in negative PET scans. Follow-up was superior to 19 months and final outcome was established as progression/relapse or no evidence of disease (NED).

RESULTS:

At the early treatment evaluation, 16/16 patients of initial staging (100%) and 2/4 of relapse (50%) achieved GRI. At the end of treatment evaluation, 14/16 patients of initial staging with GRI achieved CMR and 1/16 PMR: 14 were alive with NED in the follow-up while 1 relapsed. In the second group, 2/2 patients with GRI achieved CMR (100%): 1 continued with NED in the follow-up and another relapsed.

CONCLUSION:

 FDG-PET/CT after the first cycles of chemotherapy is useful to monitor treatment due to its high negative predictive value (87.5%), using it to modify treatment early in the non-responders.

Elsevier

Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma.

Oct 2012

Blix ES, Irish JM, Husebekk A, Delabie J, Forfang L, Tierens A, Myklebust JH, Kolstad A.

ABSTRACT

BACKGROUND: Knowledge about signaling pathways in malignant cells may provide prognostic and diagnostic information in addition to identify potential molecular targets for therapy. B-cell receptor (BCR) and co-receptor CD40 signaling is essential for normal B cells, and there is increasing evidence that signaling via BCR and CD40 plays an important role in the pathogenesis of B-cell lymphoma. The aim of this study was to investigate basal and induced signaling in lymphoma B cells and infiltrating T cells in single-cell suspensions of biopsies from small cell lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and marginal zone lymphoma (MZL) patients.

METHODS:

Samples from untreated SLL/CLL and MZL patients were examined for basal and activation induced signaling by phospho-specific flow cytometry. A panel of 9 stimulation conditions targeting B and T cells, including crosslinking of the B cell receptor (BCR), CD40 ligand and interleukins in combination with 12 matching phospho-protein readouts was used to study signaling.

RESULTS:

Malignant B cells from SLL/CLL patients had higher basal levels of phosphorylated (p)-SFKs, p-PLCgamma, p-ERK, p-p38, p-p65 (NF-kappaB), p-STAT5 and p-STAT6, compared to healthy donor B cells. In contrast, anti-BCR induced signaling was highly impaired in SLL/CLL and MZL B cells as determined by low p-SFK, p-SYK and p-PLCgamma levels. Impaired anti-BCR-induced p-PLCgamma was associated with reduced surface expression of IgM and CD79b. Similarly, CD40L-induced p-ERK and p-p38 were also significantly reduced in lymphoma B cells, whereas p-p65 (NF-kappaB) was equal to that of normal B cells. In contrast, IL-2, IL-7 and IL-15 induced p-STAT5 in tumor-infiltrating T cells were not different from normal T cells.

CONCLUSIONS:

BCR signaling and CD40L-induced p-p38 was suppressed in malignant B cells from SLL/CLL and MZL patients. Single-cell phospho-specific flow cytometry for detection of basal as well as activation-induced phosphorylation of signaling proteins in distinct cell populations can be used to identify aberrant signaling pathways.

PubMed

Bone Marrow Histopathology in the Diagnostic Evaluation of Splenic Marginal-zone and Splenic Diffuse Red Pulp Small B-cell Lymphoma: A Reliable Substitute for Spleen Histopathology?

Nov 2012

Ponzoni M, Kanellis G, Pouliou E, Baliakas P, Scarfò L, Ferreri AJ, Doglioni C, Bikos V, Dagklis A, Anagnostopoulos A,Ghia P, Stamatopoulos K, Papadaki T.

Source

*Pathology Unit †Unit of Lymphoid Malignancies ¶Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute ∥Laboratory of B cell Neoplasia, Università Vita-Salute San Raffaele, Milan, Italy ‡Hematopathology Department, Evangelismos Hospital, Athens §Hematology Department-HCT Unit, G. Papanicolaou Hospital #Institute of Agrobiotechnology, Center for Research and Technology, Thessaloniki, Greece.

Abstract

Primary splenic small B-cell lymphomas mostly comprise the distinct entity of splenic marginal-zone lymphoma (SMZL) and the provisional category of splenic lymphoma/leukemia unclassifiable, mainly represented by the hairy cell leukemia variant and splenic diffuse red pulp small B-cell lymphoma (SDRL). Until recently, histopathologic examination of splenectomy specimens was considered mandatory for the diagnosis of SMZL. However, nowadays, mainly because of advances in chemoimmunotherapy, splenectomy is performed much less frequently. We evaluated the diagnostic efficacy of bone marrow biopsy (BMB) histopathology in the diagnostic approach toward SMZL and SDRL and tested whether it may serve as a substitute for spleen histopathology in the differential diagnosis between these 2 entities. To this end, we conducted a paired assessment of BMB and spleen diagnostic samples from 46 cases with a diagnosis of SMZL (n=32) or SDRL (n=14) based on spleen histopathology. We demonstrate that detailed immunohistopathologic BMB evaluation offers adequate evidence for the confirmation of these entities and their differential diagnosis from other small B-cell lymphoma histotypes. Notably, the immunophenotypical profile of SMZL and SDRL was identical in both BMB and spleen specimens for 21 evaluated markers. Paired assessment of BMB and spleen specimens did not identify discriminating patterns of BMB infiltration, cytology, and/or immunohistology between SMZL and SDRL. Accordingly, bone marrow histopathology contributes significantly in confirming the diagnosis of SMZL and SDRL. However, presently it is not possible to distinguish SMZL from SDRL on the basis of BMB evaluation alone; hence, histopathologic examination of the spleen remains the "gold standard" approach.

PubMed