Pentostatin (Nipent) is a
nucleoside analog that irreversibly inhibits the enzyme 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. 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 noncross-resistance to 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. The observed toxicities
are listed in Table 2. In the
study by Dillman et al, 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 pentostatins 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%. This included viral,
fungal, and bacterial infections of both high and low pathogenicity.
Cummings et al 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.
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-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
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 Gk containing murine light- and heavy-chain
variable sequences and human constant region sequences. 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. 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. The pharmacokinetic
profile of rituximab remains unaffected by concomitant chemotherapy
with CHOP (cyclophosphamide, doxorubicin, Oncovin, and
prednisone). 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.
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. Among the
619 adverse events reported during therapy, 18 were grade 3 events
and two were grade 4 events (arrhythmia, 1; neutropenia, 1). 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.
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.
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