Preventing and Managing Infections in Patients Receiving Nucleoside Analogs

Introduction

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 O’Brien, MD, of M. D. Anderson Cancer Center, Houston. At the American Society of Hematology meeting last December, Dr. O’Brien 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. O’Brien. 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.

“I’m not sure whether the incidence of infections really is increased with nucleoside analogs or whether we’re 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 don’t necessarily need treatment in order to benefit the group that will do better with prophylaxis.”

Targeting High-Risk Groups for Prophylaxis

Dr. O’Brien 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,[1] 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(Drug information on 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, we’re in fact giving them what is, in effect, much higher doses of fludarabine, and this is translating into more myelosuppression and infection.”

Dr. O’Brien 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.

Potential Approaches to Minimize Infections

Dr. O’Brien 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.

“It’s 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,” she suggested.

Another trial in myeloma patients starting chemotherapy with melphalan (Alkeran) and prednisone, randomized patients to receive trimethoprim(Drug information on 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. O’Brien 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.