XIV. The rationale for combining targeted and biological anti-lymphoma drugs.

Over the past 30 years, the survival rate of patients with non-Hodgkin lymphoma and Hodgkin lymphoma has significantly improved. In the mid 1970s, patients with non-Hodgkin lymphoma were expected to have a 5-year survival of approximately 45%. In 2008, it is estimated that 60–70% of patients with non-Hodgkin lymphoma would be alive after 5 years from diagnoses. The improvement in patient’s survival is not restricted to one histologic subtype. Data from recent randomized trials and retrospective analysis of large data bases showed improvement in survival of patients with diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. Surprisingly, with the exception of rituximab, no major treatment changes were introduced over the last 30 years. For example, cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone chemotherapy that was introduced in the 1970s remains the most widely used backbone in the majority of frontline regimens. Similarly, most salvage therapy has not changed over the past three decades, with the majority being platinum-based regimens. In the meantime, our understanding of the basic genetic and biologic features of lymphoma has tremendously improved over the past few years. In the 1970s, the lymphoma diagnosis was based on the Rappaport classification that grouped lymphoma into four major categories. Today, with the use of molecular and genetic tools, more than 60 distinct subtypes of lymphoma can be identified using the WHO classification. This improved ability to precisely diagnose subset of lymphoma, however, did not translate into improvement of treatment outcome. The lack of progress is clearly not related to lack of drugs. To the contrary, the number of oncologic drugs available for evaluation in the clinical and clinical settings continues to increase. Today, there are more than 800 compounds being evaluated. On the other hand, there is an increase in the failure rate of drugs that are evaluated in phases I, and II and even phase III trials. For example, in 2011, there were 101 phase