Nucleoside analogs have marked efficacy in indolent lymphoid
malignancies, but the tradeoff is the challenge of preventing and
treating infections in these patients, according to Susan
OBrien, MD, of M. D. Anderson Cancer Center, Houston. At
the American Society of Hematology meeting last December, Dr.
OBrien discussed strategies for preventing and treating
infections in patients receiving these agents.
I would go so far as to say that these drugs have
revolutionized the treatment of some of these diseases, including
hairy cell leukemia, chronic lymphocytic leukemia, and low-grade
lymphoma, said Dr. OBrien. They are also attractive to
patients because they have less extramedullary toxicity than other
chemotherapy agents. However, there can be major complications
related to myelosuppression, immunosuppression, and infection.
Im not sure whether the incidence of infections really is
increased with nucleoside analogs or whether were simply
collecting more data and are more aware of them now, she added,
noting the dearth of clinical data on how to deal with them.
The highest rate of complications, particularly infection,
occurs among the chronic lymphocytic leukemia patients for a number
of disease-related reasons. These include hypogammaglobulinemia,
decreased cell-mediated immunity, and granulocytopenia (because of
heavy involvement of the marrow with leukemia or because of
complications of prior therapy). With disease progression and after
multiple treatments, the risk for complications grows.
This is the group for whom prophylaxis should be targeted, but
prophylaxis is a sticky concept, she noted. You will
always be treating a number of patients who dont necessarily
need treatment in order to benefit the group that will do better with prophylaxis.
Dr. OBrien advised making a decision for or against prophylaxis
based on the following factors: (1) incidence of infection, (2)
potential severity of infection, (3) ease of administering
prophylaxis, (4) potential side effects of prophylaxis, and (5) cost.
There is a need to identify high-risk groups to target for trials of
prophylaxis, she said. One such study, recently published by the
Leukemia Group at M. D. Anderson, was a retrospective evaluation
of more than 400 patients, both previously treated and untreated, who
were receiving fludarabine (Fludara)-based therapy, either alone or
in combination with prednisone. There was no age restriction, but
normal organ function was required for inclusion in this investigation.
Major infections in this retrospective analysis were defined as
pneumonia, bacteremia, sepsis, meningitis, or fever requiring
antibiotics (mostly neutropenic fevers). In the entire cohort of 400,
essentially half the patients developed at least one significant
infection during therapy with fludarabine. This was fairly evenly
divided between fevers of unknown origin, which were usually
neutropenic fevers requiring hospitalization, and pneumonia or sepsis
(equally gram positive and gram negative). These patients did not
have indwelling catheters, but the vast majority of the gram-negative
infections were Pseudomonas. Atypical infections accounted for
only 5% of the infections that occurred with fludarabine-based
therapy, she reported.
Most of the infections occurred early on, so that people who
got through the first two or three courses generally had fewer
problems with subsequent courses, presumably because they were
benefitting from a response to treatment, she observed.
By univariate analysis, the risk factors that predicted for infection
were Rai stage, prior therapy, and baseline neutropenia. Levels of
albumin and creatinine were also important (note that the trials did
not include patients with renal failure), as was level of
beta2-microglobulin; this parameter was not included in the
multivariate analysis because data were missing in a significant
fraction of patients.
There was absolutely no difference in the incidence of infections
based on treatment with fludarabine alone or with prednisone. The
only difference that emerged was an increase in atypical infections,
particularly Listeria and Pneumocystis, in patients who
received the combination.
Age was not a predictive factor for infection, although the study
included few patients over age 75 years, who might have had a higher
risk of infection, nor were CD4 counts at baseline a factor. However,
there was a higher incidence of herpes zoster reactivation in
patients with severe depletion of CD4 cells after therapy.
In the multivariate analysis, three factors were again independently
predictive of infections: prior therapy and Rai stage, as in the
univariate analysis and creatinine level. The creatinine is
interesting because there were not many patients who had a high
creatinine level (> 1.4 mg/dL, the upper limit of normal at M. D.
Anderson). My hypothesis would be that in these patients, who for the
most part are older, even mild increases in creatinine probably
represent very marked decreases in creatinine clearance. Fludarabine
is excreted largely via the kidneys, so what I would propose is that
in patients with mild renal insufficiency, were in fact giving
them what is, in effect, much higher doses of fludarabine, and this
is translating into more myelosuppression and infection.
Dr. OBrien recommended reducing the dose of fludarabine in
patients with even mild increases in creatinine by giving it for 3
days rather than 5. M. D. Anderson investigators have found that
3-day therapy maintains efficacy while reducing the incidence of
infections, she said.
Dr. OBrien then made recommendations, based on available data,
regarding the four potential approaches to minimize infection: (1)
prophylactic antibiotics, (2) growth factors, (3) intravenous
immunoglobulin (IVIG), and (4) immune stimulation.
There are no prospective data for the use of prophylactic antibiotics
with nucleoside analogs in chronic lymphocytic leukemia (CLL)
patients, she said. There are, however, retrospective data from one
study and a randomized trial in multiple myeloma. (While nucleoside
analogs are not effective in myeloma, it is reasonable to extrapolate
from this disease in terms of risk for infection during therapy, she said).
The multicenter study evaluated the activity of fludarabine in
patients with CLL and found that about half had received prophylaxis
with co-trimoxazole (trimethoprim/sulfamethoxazole), but this measure
did not protect them from hospitalization.
Its important to point out that there are no data on the
comparability of these patients in this retrospective
evaluation, she added. In fact, one could postulate that
the patients who had received prophylaxis were considered at higher
risk for infection and would have had a higher rate of
hospitalization without prophylaxis; this would mean that the outcome
was more positive in this group of patients than it might seem,
Another trial in myeloma patients starting chemotherapy with
melphalan (Alkeran) and prednisone, randomized patients to receive
trimethoprim/sulfamethoxazole twice daily for 2 months or no
prophylaxis at all. During the 2 months on prophylaxis and the
following month, the study assessed the rate of infections and looked
for a potential rebound in infections in the prophylaxis group during
the third month. There was a dramatic reduction in bacterial
infections during months 1 and 2 and some degree of benefit as well
in the third month, when the patients were off prophylaxis; there was
even a trend for a decreased mortality rate in the prophylaxis group.
This is an interesting and provocative trial, and it would be
reasonable to conduct this kind of trial in high-risk patients with
CLL, she commented. Based on very limited date, Dr.
OBrien said she would make the following recommendations:
(1) When steroids are warranted (such as in autoimmune
complications), Pneumocystis carinii pneumonia (PCP)
prophylaxis is mandatory.
(2) It is reasonable to use prophylaxis in patients who have had a
documented infection early in their treatment course and are going to
require further therapy.
(3) Based on experience in other disease states, it may be reasonable
to use prophylaxis during neutropenia, but data are lacking in the
setting of nucleoside analog use.
1. Anaissie EJ, Kontoyiannis DP, OBrien S, et al: Infections in
patients with chronic lymphocytic leukemia treated with fludarabine.
Ann Intern Med 129:559-566, 1998.
2. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, et al:
Neurologic complications of the reactivation of varicella-zoster
virus. N Engl J Med 342(9):635-645, 2000.