ADA Inhibitors: Recent Developments and Future Directions in Low-Grade Lymphoma

Pentostatin (Nipent) is a nucleoside analog that inhibits the activity of the enzyme adenosine deaminase. Inhibition of adenosine deaminase blocks the deamination of adenosine to inosine and deoxyadenosine to deoxyinosine in the purine salvage pathway. This accumulation of metabolites inhibits ribonucleotide reductase, which depletes the nucleotide pool and limits DNA synthesis. Adenosine deaminase is concentrated in lymphoid tissue, including both T and B lymphocytes. It appears that the cytotoxic effect of pentostatin is independent of intracellular concentrations of adenosine deaminase.

The 1990s marked a resurgence of interest in pentostatin, a drug that was first administered to patients with acute leukemia in the 1970s. In clinical trials, pentostatin has demonstrated response rates of 25% to 30% in heavily pretreated patients with chronic lymphocytic leukemia (CLL) and response rates of 10% to 20% in heavily pretreated patients with indolent lymphoma. Typical toxicities that occur with the use of pentostatin are cytopenias and infections.

Because patients with lymphoproliferative disorders already have an underlying immunodeficiency disorder, pentostatin causes additional depression of both T and B lymphocytes, and can make these patients more susceptible to certain opportunistic and viral infections, such as Candida, Aspergillus, Pneumocystis, and herpesvirus infections. To prevent these complications, patients with non-Hodgkin’s lymphoma (NHL) who are treated with pentostatin should be placed on prophylactic antibiotics, such as trimethoprim-sulfamethoxazole and acyclovir (Zovirax). Additionally, patients should be closely monitored for these and other infections, and should receive aggressive treatment if infection is suspected.

New Applications for Pentostatin

At a meeting in July 1999, clinical and laboratory investigators from the United States and Europe gathered to discuss new applications for pentostatin alone and in various combinations for patients with indolent NHLs. The promising data presented at this meeting form the basis for this supplement.

Dr. Fernando Cabanillas reviews the role of pentostatin and other purine nucleoside analogs in the management of indolent NHL. Dr. Nam Dang and colleagues discuss a phase II trial evaluating the role of pentostatin in relapsed/refractory T-cell lymphomas in relation to CD26 expression, which is integral to adenosine deaminase cell surface expression and function. A planned trial evaluating the use of pentostatin in combination with rituximab (Rituxan) in patients with B-cell malignancies is described by

Dr. Robert Drapkin. The use of pentostatin in combination with alkylating agents, interferon, and cordycepin is reviewed by Dr. Francine Foss. Dr. Claire Dearden concludes the supplement by describing the activity of pentostatin in primary cutaneous T-cell lymphoma.

Future studies should explore the benefit of lower-dose regimens of pentostatin to reduce toxicity, and should continue to explore the potential synergy between pentostatin and other T-cell–targeted therapeutic agents.