Non-Hodgkin Lymphoma | Page 9

Primary mediastinal large B-cell lymphoma

Clinical presentation Primary mediastinal large B-cell lymphoma (PMLBCL) occurs most often in young women (female-to-male ratio is 2:1) who present with mediastinal masses only. These masses are usually bulky and often invade surrounding structures, such as the pleura, lungs, pericardium, and chest wall, but disease is infrequently found outside the chest cavity. At recurrence, however, extranodal sites such as the lungs, adrenal glands, liver, or kidneys may be involved. Because of the location and bulk of the disease, patients complain of chest pain, cough, and shortness of breath and are often found to have superior vena cava (SVC) syndrome. This can be subtle, with unexplained breast enlargement the only symptom in some cases. The diagnosis can be delayed if the clinician does not recognize the signs and symptoms of SVC syndrome. This clinical presentation is similar to classic Hodgkin lymphoma, and indeed, that is the primary differential diagnostic consideration when these patients are evaluated.

Pathology/immunology

The pathology is characterized by a diffuse proliferation of large cells with clear cytoplasm, often accompanied by extensive sclerosis. The cells are mostly of B-cell origin and express CD20 and other B-cell markers but do not express surface immunoglobulin (Ig). Indeed, the discordant expression of CD79a and Ig expression are distinguishing features of PMLBCL. There are data that describe gains of chromosomal material in tissue specimens, most often 2p, 9p, 12q, and Xq. The rel, mal, and fig1 (interleukin-4 [IL-4] gene) oncogenes are overexpressed in tissue specimens. Ig genes have a high level of somatic hypermutation. All of these observations suggest that this entity is unique, especially compared with B-cell lymphomas that arise in peripheral nodes. IL-13 expression and downstream effectors of IL-13 signaling pathways are overexpressed, along with tumor necrosis factor (TNF) family members and TNF receptor–associated factor-1.

The overexpression of the rel oncogene, previously described, has been associated almost exclusively with the nucleus, consistent with NF-κB pathway activation, and mal gene overexpression has been confirmed in gene array studies. These data help us to reorder our thinking about these clinically unique lymphomas and to begin to build a molecular story that is consistent with the clinical observation that PMLBCL is more like classic Hodgkin lymphoma than like DLBCL. Further, the observations that certain signaling pathways are involved provide a rationale to attack these pathways specifically in a targeted approach.

Recent data have shown that amplification of 9p24 targets the immunoregulatory genes PD-L1 and PD-L2 in PMBCL and classical (nodular sclerosis) Hodgkin lymphoma (cHL). The extended amplification region also included the JAK2 locus. Amplification of JAK2 increased protein expression and activity, specifically induced PD-1 ligand transcription and enhanced sensitivity to JAK2 inhibition. The data suggest that the 9p24.1 amplification is a disease-specific structural alteration that increases both the gene dosage of PD-1 ligands and their induction by JAK2. Thus, PD-1 and JAK2 are rational therapeutic targets, and since inhibitors to PD-1 are in clinical trials, these data have important therapeutic implications for patients with PMBCL and cHL (Green et al: Blood 116:3268-3277, 2010). In addition, an excellent review of the molecular pathogenesis of PMBCL is available (Steidl C, Gascoyne RD: Blood 118:2659-2669, 2011).

As we learn more about this disorder, similarities to classical Hodgkin lymphoma become more clear but the entity of "gray zone" lymphomas, which clinically and morphologically is intermediate between cHL and large-cell lymphoma, has entered into the discussion and deserves further attention. Treatment algorithms may depend on clinical and molecular features of both disorders.

Treatment

The clinical course is variable; some report a poor outcome with conventional, CHOP-based chemotherapy regimens and irradiation, and some report an excellent outcome. It seems clear that bulk of disease and LDH level are important prognostic factors and that prediction of the outcome by the IPI is useful. A variety of chemotherapy regimens have been evaluated, including CHOP and MACOP-B/VACOP-B (methotrexate or etoposide, Adriamycin, [doxorubicin], cyclophosphamide(Drug information on cyclophosphamide), Oncovin [vincristine], prednisone(Drug information on prednisone), bleomycin), and more recently rituximab(Drug information on rituximab) has been incorporated into the management. Usually, radiation therapy is a part of the initial treatment; however, recent data suggest that radiation therapy may not be necessary in all patients. In general, in 2011, patients receive anthracycline-containing chemotherapy with rituximab, and after 4 to 6 courses, radiation therapy may be given to patients with bulky disease. There are no randomized trials comparing radiation therapy vs no radiation therapy in this setting, but in the subgroup of patients with PMBCL treated with R-DA-EPOCH, radiation was not necessary in order to achieve long-term disease-free survival comparable to historical data using radiation. Grant and colleagues discuss this in a recent review. PET scanning and early PET response may influence the use of consolidation radiation therapy in the future.

Peripheral T-cell lymphoma, unspecified

Using gene expression profiling, Iqbal et al constructed robust molecular classifying signatures for multiple T-cell lymphoma subtypes, including PTCL NOS (not otherwise specified), ALCL, AITL, and ATLL. In addition, within PTCL NOS and AITL, they were able to identify unique molecular subgroups with distinctly different survival rates (Iqbal J et al: Blood 115:1026–1036, 2010).

PTCL, unspecified is predominantly a nodal lymphoma that represents the most common T-cell lymphoma subtype in Western countries, comprising approximately 50% to 60% of T-cell lymphomas and 5% to 7% of all NHLs. PTCL usually affects male adults (1.9:1 male-to-female ratio) with a median age of 61 years (range, 17–90), with 25% of patients presenting in stage I or IIE; 12% in stage III; and 63% in stage IV. Patients with PTCL from this study commonly presented with unfavorable characteristics, including B symptoms (40%), elevated LDH level (66%), bulky tumor ≥ 10 cm (11%), nonambulatory performance status (29%), and extranodal disease (56%), leading to the majority of patients (53%) falling into the unfavorable IPI category (score of 3 to 5).

Most T-cell NHL patients are treated in the same manner as aggressive B-cell patients, with anthracycline-based combination chemotherapy such as CHOP. Randomized trials comparing CHOP with other combination regimens confirmed CHOP as a standard regimen for aggressive B-cell NHL; unfortunately, these trials do not allow for subset analysis of T-cell patients. Rituximab should not be included in the treatment of PTCL (unless other conditions such as immune thrombocytopenic purpura exist), as CD20 is not expressed. Other therapeutic agents being tested in T-cell NHL include purine and pyrimidine analogues, denileukin diftitox (Ontak), and a retinoic acid/IFN-α combination.

Denileukin diftitox is a novel recombinant fusion protein consisting of peptide sequences for the enzymatically active and membrane translocation domains of diphtheria toxin with recombinant IL-2 (CD25 receptor); it has been studied mostly in cutaneous T-cell NHL, although clinical benefit has been reported in other T-cell NHL patients.The histone deacetylase inhibitors vorinstat (Zolinza) and romidepsin (Istodax) have shown activity against PTCL. Furthermore, romidepsin recently received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of PTCL in patients who have received at least one prior therapy (see sidebar below). In addition, the FDA approved the novel antifolate pralatrexate (Folotyn) for the treatment of patients with relapsed or refractory PTCL.

Angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL), also known as angioimmunoblastic lymphadenopathy with dysproteinemia, is one of the more common T-cell lymphomas, accounting for 15% to 20% of cases and 3% to 4% of all lymphomas. Pathologically, AITL has distinct features, with a diffuse polymorphous infiltrate, prominent arborizing blood vessels, perivascular proliferation of follicular dendritic cells, and the presence of large B-cell blasts often infected with EBV. The malignant cells are mature follicular helper CD4 α β T cells. The mean age at presentation is 57 to 65 years, with a slight male predominance, and the majority of patients present with stage III or IV disease. AITL is commonly a systemic disease with nodal involvement with various associated disease features, such as organomegaly, B symptoms (50% to 70%), rash, pruritus, pleural effusions, arthritis, eosinophilia, and varied immunologic abnormalities (positive Coombs' test, cold agglutinins, hemolytic anemia, antinuclear antibodies, rheumatoid factors, cryoglobulins, and polyclonal hypergammaglobulinemia).

Spontaneous disease regression is seen on rare occasions, although AITL typically follows an aggressive clinical course. Treatment with anthracycline-based combination chemotherapy results in complete remission rates of 50% to 70% for AITL patients, although only 10% to 30% of patients are long-term survivors.

Piekarz et al reported results of a phase II trial including 47 patients with PTCL NOS and other T-cell NHLs. The overall response rate was 38%, which included a complete response rate of 18%. The median time to response was 1.8 months, while the median duration of response was 8.9 months. Responses were seen in all T-cell subtypes as well as in patients relapsed from prior autologous transplantation. The most common toxicities were nausea, fatigue, thrombocytopenia, and neutropenia (Piekarz RL et al: Blood 117:5827-5834, 2011).

One prospective, nonrandomized multicenter study treated newly diagnosed "stable" AITL patients with single-agent prednisone and combination chemotherapy for relapsing/refractory patients or initially if "life-threatening" disease was present at diagnosis. The complete remission rate was 29% with single-agent prednisone, whereas the complete remission rate for relapsed/refractory patients or patients treated initially with combination chemotherapy was 56% and 64%, respectively. With a median follow-up of 28 months (range, 7 to 53), the overall and disease-free survival rates were 40.5% (CI, 24%–56%) and 32.3% (CI, 17%–47%), respectively, although the median overall survival was 15 months.

There are anecdotal reports of relapsed AITL patients who have responded to immunosuppressive therapy, such as low-dose methotrexate/prednisone, as well as reported responses to purine analogue treatment. Furthermore, cyclosporine has demonstrated activity in relapsed AITL patients in case reports, and the ECOG is evaluating this agent in a prospective study. There are anecdotal reports of responses to thalidomide plus steroid in AITL.