Pentostatin and Rituximab in the Treatment of Patients With B-Cell Malignancies

Pentostatin (Nipent) is a nucleoside analog that irreversibly inhibits the enzyme adenosine(Drug information on adenosine) deaminase. This results in inhibition of the deamination of adenosine to inosine and of deoxyadenosine to deoxyinosine in the purine salvage pathway. The ensuing accumulation of metabolites inhibits ribonucleotide reductase, thus depleting the nucleotide pool and limiting DNA synthesis. This is the proposed mechanism of action for inhibition of rapidly proliferating cells, such as those of acute lymphoblastic leukemia.[1] Conversely, how pentostatin inhibits slowly proliferating cells, such as those of B-cell chronic lymphocytic leukemia (B-CLL), is still under investigation.

Adenosine deaminase is concentrated in lymphoid tissue, including both T and B cells; however, the cytotoxic effect of pentostatin in humans is independent of intracellular concentrations of adenosine deaminase. Response rates of 25% to 32% are seen in heavily pretreated patients with B-CLL[2-6] and indolent lymphomas.[7-9] Responses reported after treatment with 2-chlorodeoxyadenosine (cladribine, [Leustatin]), fludarabine (Fludara), and alkylating agents suggest possible non–cross-resistance to pentostatin.

Activity of Pentostatin

Pentostatin is active in CLL, achieving response rates between 18% and 35% in patients heavily pretreated with cytotoxic chemotherapy.[2-6] Phase II studies of single-agent pentostatin in heavily pretreated patients with low- or intermediate-grade NHL report response rates between 17% and 23% (Table 1).[7-9] The majority of these responses occurred in the low-grade NHL patients. Combining these reports, the response rate for pentostatin in low-grade NHL is 26%. The efficacy of pentostatin in untreated patients with CLL or NHL has not been explored.

Phase II Study

A phase II study was conducted in patients with CLL who received single-agent pentostatin at an intravenous dose of 4 mg/m²/wk for 3 weeks initially, then every 2 weeks.[3] The observed toxicities are listed in Table 2. In the study by Dillman et al,[3] severe toxicity was uncommon in the presence of normal renal function and normal bone marrow reserve. The most frequent grade 1 to 2 toxicity was nausea and vomiting, and it occurred in approximately 50% of patients. The majority of patients did not experience neutropenia or anemia.

However, infection was a major, life-threatening complication. Grade 3 to 5 infections occurred in 34% of patients. These patients were heavily pretreated, and infections are expected to occur in such immunodeficient populations. By definition, patients with B-cell malignancies have an immune deficiency, and this deficiency is increased initially by pentostatin’s depression of both T and B lymphocytes.

Phase I Study

Among the first 300 patients enrolled in a phase I trial, the overall incidence of grade 3 to 5 infections was 8%.[10] This included viral, fungal, and bacterial infections of both high and low pathogenicity. Cummings et al[9] administered pentostatin to 37 patients with refractory lymphomas and cutaneous T-cell disease at a dose of 5 mg/m²/d for 3 days, every 3 weeks. Three patients developed grade 4 infections and two died from infection.

It is important to note that these trials were conducted before the widespread use of hematopoietic growth factors.

Abating Toxicity

To prevent infectious complications, all patients with B-cell malignancies treated with pentostatin should receive prophylaxis for both viral and opportunistic infections, when indicated, with trimethoprim(Drug information on trimethoprim)-sulfamethoxazole and acyclovir. When neutropenic, patients should receive growth factor support with granulocyte colony-stimulating factor (Neupogen) or granulocyte-macrophage colony-stimulating factor (Leukine, Prokine).

Furthermore, to decrease overall toxicity, a dose of 4 mg/m² of pentostatin administered on an every-other-week schedule has been recommended.[5,11] With such a dose and schedule, it is unlikely that prohibitive toxicity will develop, making pentostatin a “patient-friendly” drug.

Background of Rituximab(Drug information on rituximab)

Rituximab (Rituxan) is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an immunoglobulin G–k containing murine light- and heavy-chain variable sequences and human constant region sequences.[12] It is produced by suspending Chinese hamster ovary cell cultures in a nutrient medium. The antibody is purified by affinity and ion exchange chromatography, resulting in a sterile, preservative-free liquid concentrate for intravenous administration.

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity.[12] Rituximab binding occurs on lymphoid cells in the thymus, in the white pulp of the spleen, and on the majority of B lymphocytes in the peripheral blood and lymph nodes.

In patients given 375 mg/m² of rituximab as an intravenous infusion, the serum half-life may be proportional to the B-cell burden and ranges from 11.1 to 104.6 hours.[13] The pharmacokinetic profile of rituximab remains unaffected by concomitant chemotherapy with CHOP (cyclophosphamide, doxorubicin(Drug information on doxorubicin), Oncovin, and prednisone(Drug information on prednisone)).[14] Administration of rituximab results in a rapid and sustained depletion of circulating and tissue-based B cells. B-cell recovery begins 6 months after 4 weekly cycles of rituximab at 375 mg/m² and returns to normal by 12 months.[13]

Pretreatment Abates Toxicity

A phase III study demonstrated a 48% (80 of 166) response rate in previously treated outpatients with low-grade and follicular B-cell lymphoma who received intravenous rituximab at 375 mg/m² once per week for 4 weeks.[15,16] Of these responses, 6% were complete responses and the remainder (42%) partial responses. Adverse events were observed during the first infusion and were generally mild. They included fever, chills, headache, nausea, vomiting, rhinitis, bronchospasm, leukopenia, and grade 1 to 2 hypotension.[14] Among the 619 adverse events reported during therapy, 18 were grade 3 events and two were grade 4 events (arrhythmia, 1; neutropenia, 1).[16] Table 3 summarizes the toxicity profile of single-agent rituximab.

The initial phase I study of rituximab used no pretreatment medications; consequently, nearly 80% of patients in that trial experienced some toxicity during the first rituximab infusion. At present, premedication with corticosteroids, antihistamines, and antiemetics is routine, and the majority of patients experience little toxicity. Rituximab, therefore, has a better safety profile compared to combination chemotherapy in low-grade malignant lymphoma.

Evaluation of the Pentostatin/Rituximab Combination

Studies previously cited in this article have confirmed that both pentostatin and rituximab have single-agent activity in B-cell malignancies, including indolent and intermediate-grade NHL, and that pentostatin is clearly active in CLL. These results led us to design a phase II multicenter trial to evaluate the safety and efficacy of pentostatin in combination with rituximab in patients with low-grade NHL and CLL. In all patients, qualitative and quantitative toxicities, as well as their duration and reversibility, will be assessed. Response rates and the durability of objective responses will also be evaluated.