Pentostatin and Rituximab in the Treatment of

Pentostatin and Rituximab in the Treatment of Patients With B
Published on Cancer Network (http://www.cancernetwork.com)
Pentostatin and Rituximab in the Treatment of Patients With
B-Cell Malignancies
Review Article [1] | June 01, 2000
By Robert Drapkin, MD [2]
Both pentostatin (Nipent) and rituximab (Rituxan) have single-agent activity in B-cell malignancies,
including indolent and intermediate-grade non-Hodgkin’s lymphoma (NHL). Pentostatin is also active
in pretreated patients
entostatin (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.[1] Conversely, how pentostatin inhibits slowly
proliferating cells, such as those of B-cell chronic lymphocytic leukemia (B-CLL), is still under
investigation.
P
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
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Pentostatin and Rituximab in the Treatment of Patients With B
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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 “patient-friendly” drug.
Background of 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, Oncovin, and 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.
Study Design and Drug Administration
Initially, the study will enroll a maximum of 25 patients with low-grade NHL and 25 patients with CLL,
with the goal of obtaining 40 evaluable patients. The study, if successful, may be expanded to
include 50 patients with low-grade NHL and 50 patients with CLL. During the first week, on day 1 of
the study, each patient will receive an intravenous infusion of rituximab at 375 mg/m². Patients will
be given pretreatment corticosteroids, antihistamines, and antiemetics as needed. On day 8, each
patient will receive the second dose of rituximab and the first dose of intravenous pentostatin at 4
mg/m². Both drugs will be repeated on days 15 and 22.
A rest period will follow after day 22, and the combination will be repeated on days 36, 43, and 50.
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After day 50, patients will be evaluated for response. Patients who progress prior to or by day 50 will
be off study. Patients with a partial response by day 50 will repeat days 8 through 50 with an
additional six cycles of both drugs. Patients in complete remission at day 50 will not require further
therapy. Figure 1 outlines the treatment scheme.
NHL Patients
Eligibility—Patients must have histologically proven low-grade NHL as defined by the International
Working Group classification.[17] They must have: (1) measurable tumor size; (2) an expected
survival of more than 6 months; (3) Cancer and Leukemia Group B (CALGB) performance status of 0
to 2 or Karnofsky performance status greater than 60%; and (4) received no more than four prior
chemotherapy drugs, not including corticosteroids or immunotherapy.
Evaluation of Response—Response to treatment will be assessed at days 57 to 64 and then at 9-week
intervals. Evaluation will be based on physical examination and imaging studies, including computed
tomography scans, magnetic resonance imaging, and other radiologic assessments of extent of
disease. The best response achieved will be considered in the analysis.
Parameters for responses are as follows: A complete response is defined as no apparent disease; a
partial response is a 50% decrease from baseline tumor size for 28 days (as measured by the
product of two perpendicular measurements) with no areas of disease progression. Stable disease is
less than a 25% increase in the size of any measurable lesion, and progressive disease is more than
a 25% increase in the size of any lesion.
CLL Patients
Eligibility—For this study, a diagnosis of B-CLL will be made according to criteria as defined by the
National Cancer Institute–sponsored working group.[18] Patients eligible for treatment must be in
the intermediate- or high-risk categories of the modified three-stage Rai staging system.[19] Patients
must be over 18 years of age; have a CALGB performance status of 0 to 2 or a Karnofsky status of
more than 60%; and must have received no more than four prior chemotherapeutic drugs, excluding
corticosteroids and immunotherapy. In low-risk Rai stage 0 patients, lymphocytosis occurs in the
peripheral blood, and is characterized by more than 5,000 lymphocytes/µL and over 3% nucleated
bone marrow cells.
Intermediate-risk Rai stage I encompasses the above criteria plus enlarged lymph nodes, while
intermediate-risk Rai stage II also includes splenomegaly and/or hepatomegaly.
High-risk Rai stage III incorporates all of the previous criteria plus anemia, as indicated by a
hemoglobin concentration of less than 11 g/dL. Rai stage IV includes the above criteria for
lymphocytosis plus a platelet count of < 100,000/µL.
Evaluation of Response—A complete response is defined as no lymphadenopathy or
hepatosplenomegaly, and a normal complete blood cell count (leukocytes > 1,500/µL, platelets >
100,000/µL, hemoglobin > 11.0 g/dL, lymphocytes < 5,000/µL). The bone marrow must also be
normal for age, with less than 30% of the nucleated cells being lymphocytes. A partial response is
defined as a greater than 50% decrease in peripheral blood lymphocytes, lymphadenopathy, and
hepatosplenomegaly. A partial response also requires: (1) a leukocyte count > 1,500/µL or a 50%
increase from initial value; (2) a platelet count > 100,000/µL or a 50% improvement from initial
value; and (3) a hemoglobin level greater than 11 g/dL or a 50% improvement from initial value.
Conclusions
Both pentostatin and rituximab have single-agent activity in B-cell malignancies, including indolent
NHL and CLL. In spite of current treatment modalities, few patients with these diseases are cured.
The combination of rituximab and pentostatin is attractive as a treatment option since both drugs
have a limited toxicity profile and can be delivered on an outpatient basis. A phase II multicenter
study will evaluate the safety and efficacy of pentostatin in combination with rituximab in patients
with previously treated and untreated low-grade NHL and CLL.
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