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Combination Therapy With Purine Nucleoside Analogs

Combination Therapy With Purine Nucleoside Analogs

ABSTRACT: Pentostatin (Nipent) has demonstrated significant activity as a single agent in patients with low-grade B- and T-cell lymphomas, but thus far, clinical experience with combinations of pentostatin and other agents is limited. A study of alternating administration of pentostatin and high-dose interferon-alfa-2a (Roferon A) in cutaneous T-cell lymphoma patients has been undertaken and has demonstrated a 41% response rate, with tolerable toxicity. Studies combining pentostatin with alkylating agents, including chlorambucil (Leukeran) and cyclophosphamide (Cytoxan, Neosar) in patients with chronic lymphocytic leukemia (CLL) have reported significant immunosuppression and have required dose modifications of one or both agents. Recently, a clinical trial was initiated to evaluate the combination of pentostatin and cordycepin, a novel purine analog, in patients with terminal deoxynucleotidyl transferase–positive acute lymphocytic leukemia, based on in vitro data demonstrating the significant synergy of this combination. [ONCOLOGY 14(Suppl 2):31-35, 2000]

Pentostatin (Nipent) has demonstrated
significant activity as a single agent in patients with low-grade B-
and T-cell lymphomas, but thus far, clinical experience with
combinations of pentostatin and other agents is limited. A study of
alternating administration of pentostatin and high-dose
interferon-alfa-2a (Roferon A) in cutaneous T-cell lymphoma patients
has been undertaken and has demonstrated a 41% response rate, with
tolerable toxicity. Studies combining pentostatin with alkylating
agents, including chlorambucil (Leukeran) and cyclophosphamide
(Cytoxan, Neosar) in patients with chronic lymphocytic leukemia (CLL)
have reported significant immunosuppression and have required dose
modifications of one or both agents. Recently, a clinical trial was
initiated to evaluate the combination of pentostatin and cordycepin,
a novel purine analog, in patients with terminal deoxynucleotidyl
transferase–positive acute lymphocytic leukemia, based on in
vitro data demonstrating the significant synergy of this combination.
[ONCOLOGY 14(Suppl 2):31-35, 2000]


Pentostatin (Nipent) has
shown single-agent activity in patients with low-grade T-cell and
B-cell non-Hodgkin’s lymphomas.[1-3] High durable response rates
have been achieved in patients with cutaneous T-cell lymphoma.[4-7]
Studies have shown a trend toward improved response rates in patients
who were previously untreated or who had received only topical
therapies, although most of the patients entered into these trials
had refractory disease. The toxicities were comparable among the
studies, with greater hematologic toxicity seen in studies that used
more intensive dosing regimens.

Pentostatin in Combination With Alkylating Agents

Thus far, the experience combining pentostatin (Nipent) with other
cytotoxic chemotherapeutic agents has been limited. A recent Eastern
Cooperative Oncology Group (ECOG) study evaluated the combination of
pentostatin (2 to 4 mg/m² on day 1) with chlorambucil (Leukeran
30 mg/m² on day 1) and prednisone (80 mg on days 1 to 5 of a
14-day cycle) in patients with B-cell chronic lymphocytic leukemia
(B-CLL) who were in sensitive first relapse or were previously
untreated.[8] Because of the increasing toxicity encountered at
higher doses, 2 mg/m² was selected as the phase II dose, and 43
patients were treated at this dose level.

The overall response rate was 87%, with a median response duration of
32 months. Grade 3 or 4 infections occurred in 33% of patients, and
included Pneumocystis pneumonia in one patient and fungal
pneumonia in two. Herpes zoster developed in 10 patients. Although
this combination was active, the incidence of opportunistic
infections was felt to be unacceptable. A subsequent trial
incorporated antibacterial and antiviral prophylaxis, while omitting
prednisone to reduce the infection rate.[9]

Dose-Escalation Trial

A dose-escalation trial examined the use of pentostatin and
cyclophosphamide (Cytoxan, Neosar) in patients with high-risk CLL who
had failed to respond to other therapies, including fludarabine
(Fludara).[M. Weiss, personal communication, November 1999] The
pentostatin dose remained fixed at 4 mg/m² and the
cyclophosphamide dose was escalated, with the first cohort receiving
600 mg/m². Thus far, seven patients have been treated, three at
600 mg/m², and four at 900 mg/m² of cyclophosphamide. The
cycles are repeated every 21 days.

All patients had biochemical evidence of tumor lysis following the
first cycle of therapy. Of three patients treated at the first dose
level, two achieved partial responses (PRs) and one a complete
response (CR). All of these responders had previous exposure to
fludarabine- and alkylating agent–containing regimens. One
patient, who was treated at the 900 mg/m² dose level, died of
progressive disease. Overall, the regimen was well tolerated, and
adverse events included mild fatigue, nausea, and vomiting. Further
study of this combination at higher dose levels is underway.

Pentostatin and Interferon

Combination therapy with pentostatin and interferon (IFN)-alfa was
first used in the setting of hairy cell leukemia to determine whether
there would be an improvement in response rates by combining two
active agents. The regimen was well tolerated.[10] Based on the high
response rates to treatment with pentostatin as a single agent in
cutaneous T-cell lymphoma patients, a similar study was initiated to
explore the combination of pentostatin and intermittent high-dose
IFN-alfa-2a (Roferon A).[11]

This study enrolled 41 refractory cutaneous T-cell lymphoma patients
with advanced skin or visceral disease. The median age was 59 years.
Cutaneous tumors were present in 15 patients, and 13 had
erythroderma. Visceral involvement was noted in seven patients, and
24 presented with blood involvement, defined as greater than 20% of
lymphocytes appearing atypical with convoluted nuclear contours on
peripheral smear. Most patients had failed to respond to multiple
previous therapies, with 25 having failed both chemotherapy and
total-skin electron-beam irradiation. Topical therapies only had been
applied to six patients, and six had received no prior therapy.

The dose and schedule of pentostatin used in this study, 4 mg/m²
daily for 3 consecutive days, was based on reports from prior phase
II studies that demonstrated the efficacy and tolerability of this
dose level. Interferon-alfa-2a was administered intramuscularly at a
dose of 10 x 106 U on day 22 and

50 x 106 U on days 23 to 26. An alternating schedule of
pentostatin and IFN-alfa had previously proven to be well tolerated
in patients with hairy cell leukemia.[10] This 42-day cycle was
repeated for up to 12 months, or until disease progression or
intolerable toxicity occurred. However, the design of the study
allowed patients who were intolerant of one of the drugs to continue
to receive the other drug on an every-21-day schedule.

Response Rates

The overall response rate was 41%, with two CRs and 15 PRs. Both
patients who achieved a CR had Sézary syndrome and diffuse
erythroderma prior to treatment. With treatment, all skin lesions and
circulating cells disappeared. A third CR, diagnosed at autopsy in a
patient with extensive plaque disease, was initially recorded as a PR
based on persistent skin abnormalities. The patient died of
gastrointestinal hemorrhage 3 months after completing therapy.
Another CR occurred in a patient thought to have stable disease after
four cycles of therapy; this patient refused further treatment and
was found on routine follow-up 2 months later to have no evidence of disease.

Responses were noted in all sites of disease, except visceral sites.
There was no correlation between response and skin stage (T1,2 vs
T3,4), presence of blood involvement, or lymph-node stage (LN2,3 vs
LN4), although patients with erythroderma had a higher response rate
(8 of 18) than those of any other skin stage (similar to studies with
single-agent pentostatin). The correlation between prior therapy and
response was not statistically significant (P = .045), unlike
earlier studies with pentostatin, which suggested a higher response
rate in untreated patients.

The overall survival duration was 15.8 months, with a trend toward
improved survival in patients who had had no prior therapy (29
months) vs those who had received prior therapy (15 months). As
listed in Table 1, the median
progression-free survival duration was 13.1 months, which compares
favorably with that of single-agent IFN studies[12] and combination
regimen studies,[13] and is superior to the survival duration
reported in our study of IFN and fludarabine.[14]

Toxicity Profile

The combination of pentostatin and IFN-alfa was well tolerated, as
demonstrated by the fact that the median projected dose of
pentostatin delivered was 92.8%, with a mean of five courses per
patient (range, 1 to 12), and the median projected dose of IFN-alfa
was 81%, with a mean of three cycles delivered (range, 1 to 8).
Pentostatin was discontinued in two patients due to toxicity, but was
not discontinued in any patients due to disease progression.
Interferon was discontinued in eight patients due to toxicity,
although these patients continued therapy with pentostatin alone.

The most frequently observed grade 3-4 toxicity was hematologic, with
granulocytopenia occurring in 15 of 41 patients. Although pentostatin
therapy has been shown to be immunosuppressive, only eight patients
developed opportunistic infections. Disseminated herpes zoster
developed in seven patients, one had central nervous system
toxoplasmosis and cytomegaloviral pneumonia, and six acquired
bacterial sepsis. Nausea occurred in five patients, and reversible
central nervous system events including confusion and headache in seven.

After infusion with pentostatin, three patients experienced
reversible bronchospasm. One of these patients had persistent
restrictive and obstructive defects on pulmonary function tests 1
year later. Another developed reversible bronchospasm and pulmonary
edema 6 days after completion of the third cycle of pentostatin.
Preclinical animal toxicology studies demonstrated
pentostatin-associated pulmonary hypersensitivity pneumonitis and
nodular pulmonary fibrosis, but other clinical trials to date have
not demonstrated significant pulmonary toxicity even at higher doses.
It is unclear what role the use of IFN in this study played in
predisposing patients to pulmonary toxicity.

In summary, this study demonstrated that the combination of
pentostatin and intermittent high-dose IFN was well tolerated and was
associated with a high response rate and an impressive response
duration, especially in patients with Sézary syndrome. The
frequent incidence of granulocytopenia may have been due to the
high-dose of IFN, as most patients who discontinued therapy due to
toxicity stopped taking IFN, not pentostatin.

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