Dr. Rafael Conti. Oncology and Hematology Department, Alexander Fleming Institute, Buenos Aires, Argentina

Introduction

Lymphomas are a heterogeneous type of neoplasms of the lymphatic system, which are produced by failures in lymphocyte maturation and functioning.  Basically, they are divided in two broad groups: Hodgkin lymphomas and non-Hodgkin lymphomas (NHL).
Within the NHL group, we must take into account that the clinical context depends on the aggressiveness degree and the CD20-antigen expression capacity. This is necessary to be able to sub-divide them (table 1) in B-cell or T-cell lymphomas, and indolent, aggressive or very aggressive lymphomas^{1 2}.
The clinical relevance of this division leads us to the following considerations^{3 4}:

• Patients with indolent lymphomas have a prolonged survival, which can be measured in years, even without treatment and, besides, they are not cured with the available treatments. We can only achieve long periods of disease remission, with a continuous tendency to relapse and the eventual transformation to more aggressive forms.
• On the other hand, the aggressive lymphomas and the very aggressive forms have more chances of being cured, but they are rapidly fatal when they are not timely treated or when the first therapeutic lines fail, with a survival which is measured in months.

Based on these progressive considerations according to the treatment, we shall review these lymphomas separately.

Indolent lymphomas

They represent the 35-40% of the NHLs. The most common sub-types are: follicular lymphoma (22%), small cell lymphocytic lymphoma (6%), mantle cell lymphoma (6%) –this sub-type can have aggressive forms– and marginal zone lymphoma (5), and with less than 1%: lymphoplasmacytic lymphoma, mycosis fungoides/Sezary syndrome and splenic marginal zone lymphoma.
With the low chances of achieving the disease cure –unlike the aggressive forms–, the therapeutic management of patients with indolent lymphomas must respect the aim of being ordered when it is necessary to control the symptoms. This includes:

• local symptoms due to progression or bulky nodal disease
• compromise of the normal functioning of an organ due to progression or bulky disease
• presence of B symptoms
• presence of symptomatic extranodal disease, as pleural effusion or ascites
• cytopenias due to excessive infiltration of the bone marrow, autoimmune disease, thrombocytopenia or hypersplenism
• patient's insistence

Rituximab: monoclonal antibodies

The appearance of the monoclonal antibodies has been the most important advance in the last 20 years in the therapeutic arsenal against lymphomas. This treatment alternative stands out for its efficacy and low toxicity. Besides, its combination with chemotherapy increases the response rates both in follicular lymphomas and in aggressive B-cell lymphomas.
Rituximab is the first monoclonal antibody authorized for NHLs. It has the function of combining with a specific protein, the CD20 antigen, which is found in the normal B-cell surface and in neoplastic cells too. This binding has the effect of reactivating the immune system, recruiting natural defenses of the organism and eliminating marked B-cells. The stem cells –progenitors of B cells– in the bone marrow lack the CD20 antigen, which enables the healthy B cells to regenerate after treatment and recover their normal levels within some months.
Rituximab was first ordered as monotherapy for patients with recurrent follicular NHLs or refractory patients. Afterwards, since 2002, it received the European approval for the treatment of aggressive NHLs in combination with chemotherapy with cytoxan, hydroxirubicin (adriamycin), oncovin (vincristine) and prednisone (CHOP regimen). Besides, in 2004, it was approved as first-line treatment for follicular NHLs, in combination with chemotherapy with cyclophosphamide, vincristine and prednisone (CVP regimen). From that moment, therapy with monoclonal antibodies received great attention for the treatment of NHLs, mainly focused in the aggressive and indolent forms.
The action mechanism for the efficacy of rituximab includes antibody-mediated apoptosis, complement-mediated cytotoxicity and antibody-dependent cytotoxicity. Regarding this latter action mechanism, retrospective studies suggest that there is some polymorphism of the immunoglobulin (Ig) G Fc receptor which could affect the activation and function of the cellular cytotoxicity and, this way, predict the response to rituximab of patients with follicular NHLs.
The highest toxicity of its use is related with the infusion speed: fever, shivers and hypotension which are general more severe with the first infusion, and less severe in the subsequent cycles. A small number of patients has mucocutaneous reactions.