Biological and Clinical Prognostic Factors in SMZL
The median overall survival in SMZL ranges between 5 and 10 years, but in cases of aggressive disease, seen in approximately one-third of patients, median survival is less than 4 years. Clinical and biological prognostic factors have been identified by several investigators (Table 2). The Italian Intergroup of Lymphomas (IIL) has developed a prognostic model based on the tracking of three factors (hemoglobin level less than 12 g/dL, lactate dehydrogenase level greater than normal, and albumin level less than 3.5 g/dL) in 309 patients, leading to a prognostic index. This index allows one to separate patients into three groups, each with a different 5-year survival rate: 88% in the low-risk group (no risk factors), 73% in the intermediate-risk group (one risk factor), and 50% in the high-risk group (more than one risk factor). However, this index has not yet been demonstrated to have any therapeutic implications. In this analysis, the International Prognostic Index (IPI) was found to predict survival, although the multivariate analysis selected the three indicated parameters. Other biologic prognostic factors have been described based on gene expression analysis; these include expression of CD38, unmutated IGHV gene status, and expression of NF-κB–activated genes.
Histologic transformation to large-cell lymphoma remains uncommon, occurring in 10% to 20% of patients. Diffuse large B-cell lymphoma, when it involves the spleen, is usually characterized by one or several large nodules, very rarely involving the bone marrow. Transformation occurs within a median interval ranging from 12 to 85 months. The transformation presents clinically as the appearance of general symptoms, an increase in LDH level, and disseminated lymphoma involvement. After histologic progression, the median survival time is shortened to 26 months.
New Therapeutic Strategies in SMZL
Treatment is required only in symptomatic patients with painful splenomegaly, with or without associated cytopenia due to hypersplenism. Asymptomatic patients, who constitute a large percentage of patients, can be appropriately managed with watchful waiting for several years. Withholding treatment does not influence the course of disease, and these patients often have stable disease for at least 10 years. The only exception to this management approach is in the setting of SMZL associated with active HCV infection. Antiviral therapy with pegylated interferon-α and ribavirin(Drug information on ribavirin) will lead to clearance of HCV RNA in 75% of patients and to concomitant clinical remission of the lymphoma.
When patients become symptomatic because of anemia (hemoglobin level < 10 g/dL), abdominal pain, thrombocytopenia (platelet count < 80 × 109/L), several treatment options may be proposed to them. Splenectomy will rapidly improve performance status and correct anemia, thrombocytopenia, and neutropenia within 6 months of the procedure. This improvement is maintained for years, with a median period of freedom from treatment of 8 years, even if bone marrow and blood lymphocytosis persist, suggesting a partial response. Adjuvant chemotherapy following splenectomy provides an increased remission rate without modifying relapse-free and overall survival. For patients who are unfit for splenectomy or unwilling to undergo surgery, systemic therapy may be effective (Table 3). Rituximab(Drug information on rituximab) (Rituxan) alone is reported to provide an excellent response rate, with a shorter progression-free survival than that observed when rituximab is combined with cladribine(Drug information on cladribine) or fludarabine or polychemotherapy.[8,19,45-50] Recently, bendamustine (Treanda) has emerged as a highly effective drug for NHL, including MZLs. A European trial evaluating the combination of rituximab and bendamustine in patients with MZLs is scheduled to begin in the near future (EudraCT number 2011-000880-28). For clinical trials to be evaluated, however, it is necessary to develop consistent staging and response criteria for the disease. The recent workshop of the International MZL group has redefined these parameters (Table 4).
SMZL is considered to be a distinct entity among NHLs, with definite clinical and morphological characteristics. Although this entity is characterized by very different clinical presentations, strong similarities in the epidemiology and the biology of the tumor cells support a common origin in the memory B cells of the marginal zone. In the past 5 years, a large collaborative effort by biologists, pathologists, and clinicians has resulted in agreement on more stringent criteria for the diagnosis of the disease and for the evaluation of clinical response. These efforts should support the design of further prospective clinical trials to define the optimal therapeutic approach to this disease.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.