Lymphoma

In Sweden about 2,000 patients are diagnosed each year with malignant lymphoma. The vast majority, approximately 90% of these are derived from B-lymphocytes, B-cell lymphomas. Smaller fractions, about 10%, are T and NK cell lymphomas. Some exhibit a rapid and aggressive course, i e aggressive lymphoma, while others are slowly proliferative, indolent chronic malignancies.

The most common subtype (approximately 500 cases per year, 25%) is Diffuse large B cell lymphoma (DLBCL). With modern chemoimmunotherapy, approximately 50% of patients with this type of lymphoma are cured. This is a heterogeneous disease, clinically and biologically, and by way of gene expression profiling, two major subtypes have been identified – germinal center type (GCB) and activated B-cell type (ABC), with distinct biological properties. So far, the treatment is the same for all patients.

Follicular lymphoma (FL) is the second most common lymphoma type. Most of these tumors are slow-growing tumors with indolent course, and are currently considered not curable with conventional therapy.

Mantle cell lymphoma (MCL) is a relatively rare B-cell lymphoma, with approximately 75 cases per year, which morphologically appears as an indolent lymphoma, but usually has a very aggressive clinical course. Early treatment strategies, such as the first Nordic treatment protocol (MCL1) were unsuccessful, with all patients eventually relapsing. Recently, however, results from the second Nordic Lymphoma Group (MCL2), including chemoimmunotherapy and high-dose chemotherapy with autologous stem cell support, indicate that about two thirds of patients achieve prolonged remission and perhaps even cure.

For older patients, there is no established standard therapy. Promising results have been seen with a combination of rituximab and a new chemotherapeutic agent, bendamustin. Another effective and well tolerated treatment is the immune activating and angiogenesis inhibiting agent lenalidomide. We have therefore undertaken a new Nordic study with a combination of lenalidomide, bendamustin and rituximab for elderly patients. The treatment of MCL is quite different from that of other B-cell lymphoma, and it is therefore imperative that early identification of this type of lymphoma, which requires specific treatment.

MAIN AREAS OF RESEARCH

• Diagnostics
• Clinical trials 
• Epidemiology / Biobanks

Diagnostics

SOX11 - new marker for mantle cell lymphoma

Mantle cell lymphoma (MCL) is diagnosed usually by expression of the protein cyclin D1. A proportion of the tumors are cyclinD1-negative. Our group has found that the expression of a protein, not previously associated with lymphoma, SOX11, appears to be specifically overexpressed in the nucleus of both cyclinD1 + and cyclinD1 tumors. As MCL requires specific treatment, it is highly important to further improve the diagnostic setup for identifying this disorder, and to clarify the diagnostic value of SOX11, have explored this in a larger material. We are also working to clarify the function and regulation of SOX11 in MCL.

Prognosis and prediction in Diffuse Large B-cell lymphoma

CD40

We have in previous studies demonstrated that overexpression of CD40 on tumor cells is associated with favorable prognosis in patients with diffuse large B cell lymphoma, DLBCL. We currently try to explain the background to why the increased CD40 expression increases sensitivity to chemotherapy. With gene expression profiling CD40+ and CD40-negative tumors are compared, and the findings verified on protein level using immunohistochemistry.

Development of targeted treatment in DLBCL

We have developed a model to study chemotherapy sensitivity in vitro, with five different DLBCL cell lines, with different chemotherapy sensitivity, which expresses one or more of these resistance genes. These will be used to study the effect of protein inhibitors in combination with chemotherapy and antibody treatment in vitro.

Clinical trials

Diffuse Large B-cell lymphoma (DLBCL) - treatment based on biological subtypes

Primary Treatment

The standard treatment of this disease is at present chemotherapy (CHOP) in combination with an antibody (rituximab), R-CHOP. The antibody rituximab is directed against the surface protein, CD20, which is expressed on the majority of B-cell lymphomas. Currently, the same treatment is given regardless of subtype. In a small study of patients with relapsed DLBCL a proteasome inhibitor, bortezomib was added to and rituximab and chemotherapy. The efficacy in a subgroup of DLBCL, activated B-cell (ABC), was superior compared to that of the GCB subtype- overall response 83% vs 13%, P <.0012. Within the framework of the Nordic Lymphoma Group, we plan to take part in a randomized Phase III trial, initiated by the British Lymphoma Group, to study the value of the addition of bortezomib to R-CHOP, including prospective gene expression profiling on formalin fixed material (Illumina DASL). This trial is planned to include 940 patients, and start the final quarter of 2010.

Second-line treatment

In a small study, still unpublished, with the drug lenalidomide, was significantly better results for patients with ABC-type compared with GCB (overall response 78% vs 22%). We will participate in a company-sponsored study to examine whether these results can be confirmed in a larger material. Also this study includes prospective gene expression profiling, but on fresh frozen tissue.

Mantle cell lymphoma

Primary Treatment - young patients

Within the framework of the Nordic Lymphoma Group, we will initiate a follow-up study of patients <65 years, with the intensification of chemotherapy with high dose cytarabine alone for patients with high risk disease (MIPI high risk).

Primary Treatment - older

For this group, where there is no established standard primary treatment, we have initiated a Phase I-II trial to study the addition of lenalidomide and rituximab to bendamustin. The study is run by the Nordic Lymphoma Group, and is coordinated in Lund. The Phase I portion, with the aim of determining the maximum tolerated dose of lenalidomide in this combination, nine patients have enrolled so far in the Sweden and Norway. A total of 60 patients are to be included

Peripheral T-cell lymphoma (PTCL) - the addition of alemtuzumab

Standard treatment for PTCL has been chemotherapy combination of CHOP with or without subsequent high-dose chemotherapy. The antibody alemtuzumab in a phase II study in which we participated, showed good therapeutic effect in approximately one third of patients. In two Phase III studies, the first for this patient, we therefore investigate whether the addition of alemtuzumab improves the survival of this disease (ACT 1 and ACT 2), which started in 2008 and 2010 respectively. Also in these trials, we serve as the national principal investigator site.

Epidemiology / biobank

In a series of sub-project, we intend to exploit the population-based Swedish Lymphoma Registry to investigate the treatment results in various types of primary treatment in DLBCL and FL, as a complement to randomized clinical trials. This is run in collaboration with the Oncological Centre in Lund.

Specific questions

• Does the R-CHOP-14 improve overall survival in DLBCL compared with R-CHOP-21?
  - Globally?
  - In subgroups according to the IPI?
• What is the outcome in terms of overall and relative survival by clinical prognostic factors, including IPI, and presentations of the disease in a population-based dataset?
• How has the survival, total + relative, changed over the time period?
• Has the incidence has changed over the time period?
• What are the treatment results in terms of overall survival with rituximab compared with R-CHOP in FL?
  - Globally?
  - In the subgroups according to the FLIPI?
• What is the validity of data in the register in relation to patient data?