Systemic Anaplastic Large-Cell lymphomas

Anaplastic large-cell lymphoma (ALCL) is a widely recognized clinico-pathological entity that is characterized by: frequent occurrence in children (approximately 40% of all large-cell lymphomas), presence of large anaplastic tumor cells expressing the CD30 molecule (previously named Ki-1), male predominance, and highly aggressive clinical course usually associated with systemic symptoms and extra-nodal involvement, particularly skin and bone. The term anaplastic large-cell lymphoma has been limited only to cases with T and null phenotype and the lymphoma accounts for 2 to 3% of all non-Hodgkin’s lymphoma. This lymphoma is frequently associated with the presence of the chromosomal translocation t(2;5)(p23;q35) (a cytogenetic abnormality) that results in the expression of a protein in the tumor cells called nucleophosmin-anaplastic lymphoma kinase or NPM-ALK (found in approximately 60% of all cases of this lymphoma); this protein can be detected in the tumor sample using a technique called immunohistochemistry and several studies have demonstrated that its expression is a prognostic biomarker.

ALCL often has an aggressive clinical course for which combination therapy is warranted. An excellent outcome has been reported for this type of lymphoma occurring in pediatric and adult patients treated with combination chemotherapy; the 5-year disease survival after aggressive chemotherapy is approximately 70%. However, recent studies have reported on the prognostic importance of NPM-ALK protein, with positive cases usually showing better survival. NPM-ALK positive tumors are usually seen in younger patients, have higher incidence of extra-nodal involvement, and have a higher male predominance; the 2-year disease free survival is approximately 84% (only 52% for patients in which tumors are not expressing the protein) and the 5-year disease free survival is approximately 72% (only 30% for patients in which tumors are not expressing the protein). Thus, additional agents are needed to improve the prognosis, especially for those tumors with no expression of the NPM-ALK protein.

The use of antibodies against tumor-associated antigens (markers specifically expressed in tumor cells but not in normal cells) as anticancer therapy was first proposed 100 years ago by Paul Ehrlich. The development of the hybridoma technique (a laboratory technique) described by Kohler and Milstein in 1975 allowed the production of monoclonal antibodies and enabled a more rigorous assessment of their clinical role in anticancer therapy. Furthermore, molecular engineering techniques have allowed the development of specific antibody molecules with more desirable characteristics for therapy in humans. The use of antibodies against tumor-associated antigens may result in tumor cell lysis involving complement-mediated cytotoxicity or antibody-dependent cellular cytotoxicity in which the patient’s own immune system attacks and removes malignant cells. In addition, the antibody bound to the tumor-associated antigen may interfere with vital pathways for the survival of the tumor cells. The development of monoclonal antibodies against B-cell markers in non-Hodgkin’s lymphomas (not expressed in ALCL) has revolutionized the treatments of these malignancies. Rituxan® alone or in combination with chemotherapy is the best example of anticancer activity of these agents.

ALCL expresses the CD30 molecule and a monoclonal antibody has been developed against it (SGN-30). SGN-30 has demonstrated anti-tumor activity in preclinical studies, and is currently being evaluated in clinical trials for patients with systemic ALCL. From these studies the safety of the antibody has been demonstrated and preliminary anti-tumor activity has been observed. An example is a 4-year-old female who was diagnosed with ALCL of the left breast (NPM-ALK negative). The patient was treated with multiple schemas of chemotherapy with a very poor response (CHOP, DHAP, CVAD), and also failed surgery (mastectomy). She participated in one of the studies evaluating SGN-30 and after 6 weekly doses of 6 mg/kg the tumor mass disappeared (see the figure below). The enlarged lymph nodes in the axilla regressed to normal size and pain symptoms were relieved. This patient has been in complete remission for 19+ months (as of December 2005).