Monoclonal antibodies in the treatment of chronic lymphoid leukemias

Abstract

In recent years preclinical and clinical studies have been undertaken with selected monoclonal antibodies (MoAbs) either alone or coniugated to toxins in patients with several lymphoid malignancies, including chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL) and hairy cell leukemia (HCL). Two MoAbs, directed against CD20 antigen (Rituximab, RIT) and CD52 antigen (Campath-1H, alemtuzumab, ALT) demonstrate significant activity in CLL. The most notable success to data has been achieved with ALT, both in previously treated and untreated patients with CLL. ALT is a humanized rat IgG1 antibody that binds to the cell membrane of virtually all normal as well as malignant lymphocytes. In the vast majority of CLL patients ALT causes constant reduction of abnormal blood lymphocytes, usually in less than 4 weeks, and disappearance of CD5/CD19 co-expression cells from blood. The regression of lymphoid infiltration from other sites is less clear. ALT is also highly active in patients with CLL in progression, even refractory to fludarabine (FA). Hematological toxicity, especially long-lasting lymphocytopenia, was noted in the majority of patients. The most important clinical side effects of ALT treatment were infections, mainly herpes simplex virus and cytomegalovirus reactivation. RIT is also active in CLL in conventional doses. However some studies suggest that higher doses are more effective than standard doses, used routinely in other lymphoid malignancies. The activity of ALT and RIT in CLL patients resistant to FA and their synergistic interactions with cytotoxic drugs suggests that a combination of these agents may lead to further progress in the treatment of this disease. The T-cell variant of PLL has demonstrated impressive responses to ALT in several trials even if the patients were refractory to deoxycoformycin (DCF) and other agents. However, this MoAb is not curative, because all patients eventually relapsed. Consequently, treatment with ALT may need to be associated with stem cell transplantation to consolidate and maintain long-term remissions. Recently anti-CD22 and anti-CD25 immunotoxins have been investigated in purine analogues refractory or relapsed HCL. The presented results indicate that these agents are highly active and well tolerated even if the patients were resistant to 2-CdA or DCF.