Non-Hodgkin Lymphoma

Anaplastic large-cell lymphoma, T-/null-cell, primary systemic type

Anaplastic large-cell lymphoma (ALCL), primary systemic type, is a CD30+ T-cell lymphoma that accounts for approximately 2% to 3% of all NHLs. This disease mainly involves lymph nodes, although extranodal sites may be involved (not exclusively the skin; see subsection on ALCL, CD30+ cutaneous type). This disease may be divided in part based on the expression of the tyrosine kinase anaplastic lymphoma kinase (ALK), created from a balanced chromosomal translocation t(2;5) and other less common translocations involving 2p23 (see Table 1). When heterogeneous patient populations are analyzed, the prevalence of ALK positivity in primary systemic ALCL cases is 50% to 60%. ALK-positive ALCL is typically diagnosed in men prior to age 35 (male-to-female ratio, 1.7:1), with frequent systemic symptoms and extranodal and advanced-stage disease. ALK-negative patients are usually older (median age, 61 years), with a male-to-female ratio of 1.5:1, with a similar high incidence of extranodal disease.

In addition to the prognostic importance of ALK positivity, the IPI has been identified as an independent prognostic factor within the group of ALK-positive ALCL patients, with a reported 5-year overall survival of 94% vs 41% for IPI 0 or 1 and 2 to 4, respectively. This better prognosis is apparent despite the fact that ALK-positive patients more commonly present with a poorer performance status and more advanced-stage disease compared with ALK-negative patients.

Therapy for pediatric ALCL is often based on prognostic risk factors, with treatment regimens modeled after high-grade B-cell NHL protocols. Following a brief cytoreductive prephase, short, intensified polyagent chemotherapy is administered, with the number of cycles dependent on the stage of disease. Therapy for adult ALCL, primary systemic type, has commonly included anthracycline-based regimens such as CHOP. Autologous hematopoietic SCT in first complete remission for ALK-negative ALCL has been advocated by some groups, although this approach warrants prospective validation. The immunoconjugate, brentuximab vedotin (SGN-35), an anti-CD30–antibody linked to the antitubulin agent, monomethyl auristatin E (MMAE), has shown remarkable clinical activity against this disease (see sidebar).

Hepatosplenic T-cell lymphoma

Hepatosplenic T-cell lymphoma (HSTCL) is an uncommon T-cell lymphoma that is seen mainly in young males (median age, 35) presenting with B symptoms, prominent hepatosplenomegaly, mild anemia, neutropenia, thrombocytopenia (commonly severe), significant peripheral blood lymphocytosis, and rare lymphadenopathy. It is associated with an aggressive clinical course (median survival, 12 to 14 months).

The tumor cells are usually negative for CD4 and CD8 (85%); positive for CD2, CD3, and CD7 (negative for CD5); and express CD56 in 70% to 80% of cases. TIA-1 is present in almost all cases, but commonly granzyme B and perforin are not present, an indication of a nonactivated cytotoxic T-cell phenotype. Cells usually express the γ/δ T-cell receptor (Vd1+/Vd2–/Vd3–) but are negative for EBV.

Historically, patients with HSTCL have been treated with CHOP-like regimens. Early autologous SCT has been favored by some investigators based on anecdotal cases; however, if feasible, an allogeneic transplant may be more appropriate. A recent report described activity with the purine analogue pentostatin in relapsed HSTCL patients. Approximately 10% to 20% of HSTCL cases arise in immunocompromised patients, predominantly in the solid-organ transplant setting.

Extranodal NK/T-cell lymphoma, nasal-type

Extranodal NK/T-cell lymphoma, nasal-type, formerly known as angiocentric lymphoma, is rare in Western countries, being more prevalent in Asia and Peru. The disease commonly presents in men at the median age of 50 years. This entity is associated with EBV and is typically characterized by extranodal presentation and localized stage I/II disease but with angiodestructive proliferation and an aggressive clinical course. These tumors have a predilection for the nasal cavity and paranasal sinuses ("nasal"), although the "nasal-type" designation encompasses other extranodal sites of NK/T-cell lymphomatous disease (skin, GI, testis, kidneys, upper respiratory tract, and rarely orbit/eyes).

Combined-modality therapy incorporating doxorubicin(Drug information on doxorubicin)-based chemotherapy (minimum of 6 cycles for patients with stage III or IV disease) and IFRT (minimum 50 Gy), is recommended for patients with extranodal NK/T-cell lymphoma, nasal type, although the benefit of the addition of chemotherapy to radiation therapy has not been confirmed for limited-stage disease. A phase I/II study of concurrent chemoradiotherapy for untreated localized NK-/T-cell lymphoma was conducted in Japan showing a 2-year overall survival of 78%, although confirmatory studies are warranted. Patients with systemic disease have poor long-term survival (5-year overall survival, 20% to 25%), with high locoregional (over 50%) and systemic failure rates (over 70%). Asparaginase (Elspar) has been shown to have significant activity against this lymphoma, typically integrated with other agents, such as the regimen SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide).

Enteropathy-associated T-cell lymphoma

Enteropathy-associated T-cell lymphoma (EATL; also known as intestinal T-cell lymphoma) is a rare T-cell lymphoma of intraepithelial lymphocytes that commonly presents with multiple circumferential jejunal ulcers in adults with a brief history of gluten-sensitive enteropathy. EATL accounts for less than 1% of NHLs, according to the ILSG, and has been recognized to have a poor prognosis, with reported 5-year overall and disease-free survival rates of 20% and 3%, respectively. This finding is in part related to many patients presenting with a poor performance status and varied complications of locally advanced disease by the time a diagnosis of EATL has been confirmed.

EATL may present without an antecedent celiac history, but most patients have abdominal pain and weight loss. Evidence of celiac serologic markers such as positive antigliadin antibodies and/or HLA types such as DQA1*0501/DQB1*0201/DRB1*0304 may be present at diagnosis of EATL. Moreover, these genotypes may represent celiac patients at higher risk for development of EATL. Small bowel perforation or obstruction, GI bleeding, and enterocolic fistulae are recognized complications of this disease. The immunophenotype consists of pan–T-cell antigens, usually CD8+, and the mucosal lymphoid antigen CD103 is often expressed.

Following diagnosis of EATL, doxorubicin-based combination chemotherapy should be considered for each patient, and aggressive nutritional support with parenteral or enteral feeding is critical in the care of these patients. Patients with known celiac disease should adhere to a gluten-free diet.

Adult T-cell leukemia/lymphoma

The retrovirus HTLV-1 has been documented to be critical to the development of ATLL. HTLV-1 is known to cause diseases other than ATLL, including tropical spastic paraparesis/HTLV-1–associated myelopathy, infective dermatitis, and uveitis. In endemic areas in Japan, approximately 10% to 35% of the population is infected with HTLV-1. Among these carriers, the overall risk of ATLL is approximately 2.5% in patients who live to age 70. Of the Caribbean population, 2% to 6% are HTLV-1 carriers, whereas less than 1% of the population in lower-risk areas, such as the United States and Europe, are seropositive. HTLV-1 is transmitted through sexual intercourse, transfused blood products (products containing white blood cells, not fresh frozen plasma), shared needles, breast milk, and vertical transmission. Transfusion of HTLV-1–contaminated blood products results in seroconversion in approximately 30% to 50% of patients, at a median of 51 days.

The clinical features of 187 ATLL patients included a median age at onset of 55 years, lymphadenopathy (72%), skin lesions (53%), hepatomegaly (47%), splenomegaly (25%), and hypercalcemia (28%) present at diagnosis. The differential diagnosis between cutaneous ATLL and mycosis fungoides is often difficult. ATLL is separated into four subtypes divided by clinicopathologic features and prognosis: acute, lymphoma, chronic, and smoldering. Shimoyama and colleagues reported on the characteristics of 818 ATLL patients. Patients with acute-type ATLL present with hypercalcemia, leukemic manifestations, and tumor lesions and have the worst prognosis, with a median survival of approximately 6 months. Patients with lymphoma-type ATLL present with low circulating abnormal lymphocytes (< 1%) and nodal, liver, splenic, CNS, bone, and GI disease; the median survival is 10 months. Patients with chronic-type ATLL present with > 5% abnormal circulating lymphocytes and have a median survival of 24 months, whereas the median survival of patients with smoldering-type ATLL has not yet been reached.

ATLL is an aggressive neoplasm with resistance to conventional chemotherapy, in part due to the viral protein Tax-mediated resistance to apoptosis and overexpression of p-glycoprotein (the product of the multidrug resistance-1 gene). Patients may initially respond to combination chemotherapy, but unfortunately, response durations are brief (5 to 7 months). El-Sabban and colleagues combined arsenic trioxide (Trisenox) with IFN-α, which induced cell-cycle arrest and apoptosis. Response rates of 70% to 90% to combination IFN-α and zidovudine therapy have been demonstrated in ATLL, with associated increased median survival rates compared with those of historic controls. The Japanese Clinical Oncology Group Study (JCOGS)randomized untreated aggressive ATLL to VCAP-AMP-VECP vincristine, cyclophosphamide(Drug information on cyclophosphamide), Adriamycin [doxorubicin], prednisone(Drug information on prednisone)-Adriamycin [doxorubicin], MCNU [ranimustine], prednisone-vindesine, etoposide, carboplatin, prednisone) chemotherapy vs biweekly CHOP. They reported a higher complete remission rate and improved survival rates with VCAP-AMP-VECP, although treatment-related toxicity was high. Allogeneic SCT has been successfully employed in select patients.

Other agents with anecdotal activity in ATLL include irinotecan and the purine analogues (pentostatin and 2-chlorodeoxyadenosine, although pentostatin did not appear to improve outcomes when added to combination chemotherapy). Future research should include the investigation of recombinant toxins and antibodies, such as denileukin diftitox and alemtuzumab(Drug information on alemtuzumab). Allogeneic SCTs have also been incorporated into the treatment strategies.