Original Article
Cost Effectiveness of Prophylactic Intravenous Immune Globulin in Chronic Lymphocytic Leukemia
N Engl J Med 1991; 325:81-86July 11, 1991
- Abstract
- Abstract
Background
A recent randomized controlled trial of intravenous immune globulin in patients with chronic lymphocytic leukemia and hypogammaglobulinemia demonstrated a statistically significant reduction in the rate of bacterial infections among patients who received intravenous immune globulin. We used decision-analysis techniques to determine whether prophylactic intravenous immune globulin is likely to result in an overall clinical benefit to patients who receive this treatment and to examine its cost effectiveness.
Methods.
We constructed a model to compare two strategies: treatment with intravenous immune globulin at a dose of 400 mg per kilogram of body weight every three weeks and no immune globulin therapy. Baseline estimates of the efficacy of intravenous immune globulin were derived from the published results of the randomized trial. The costs of treatment, complications, and infections were estimated on the basis of component costs. Health outcomes were measured in terms of gains in quality-adjusted life expectancy.
Results.
Intravenous immune globulin therapy can result in a loss of quality-adjusted life expectancy when the inconvenience of treatment is taken into account. If the inconvenience of treatment is not considered, therapy results in a gain of 0.8 quality-adjusted day per patient per year of therapy at a cost of $6 million per quality-adjusted life-year gained.
Conclusions.
Decision-analysis modeling may be applied to the results of randomized controlled trials to assess the potential clinical and financial effects of adopting the intervention in medical practice. In the case of intravenous immune globulin therapy in patients with chronic lymphocytic leukemia and hypogammaglobulinemia, this type of analysis suggests that treatment might not result in improved quality or length of life and that it is extraordinarily expensive in comparison with other treatments generally accepted as cost effective. (N Engl J Med 1991; 325: 81–6.)
Media in This Article
Table 1
Base-Line Estimates of the Efficacy of Intravenous Immune Globulin.Table 2
Relative Quality Adjustments for Clinical States.*Article Activity
- Article
IN a recent double-blind study, the Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia randomly assigned patients with chronic lymphocytic leukemia who were at high risk for infection to receive intravenous immune globulin or placebo.1 The groups were compared both with respect to survival and with respect to the rate and severity of infection during the one-year period of treatment. The study demonstrated a statistically significant decrease in the number of bacterial infections in the treated group, without a decrease in mortality at one year. On the basis of this trial and several uncontrolled or smaller studies,2 3 4 5 a number of authors have advocated prophylactic treatment with intravenous immune globulin for patients with chronic lymphocytic leukemia and hypogammaglobulinemia.6 7 8 9 10
Unlike vaccination, which produces prolonged immunity, passive immunization with immune globulin provides transient protection, which lasts only until the antibody is cleared. The need for frequent administration combined with the high unit cost of intravenous immune globulin results in high treatment costs, whether measured in terms of patient time or medical resources. Using the results of the Cooperative Group trial as our source of estimates of the efficacy of intravenous immune globulin, we used decision-analysis techniques to determine whether a reduction in bacterial infections was likely to result in a net clinical benefit to patients. Estimates of costs were derived from component costs and quality adjustments from physicians' assessments of the quality of life in a variety of clinical states. These simple techniques, which required little empirical investigation, were used to obtain a first approximation of the cost-effectiveness ratio of intravenous immune globulin; the results obtained with this model suggest that more precise measurement is unnecessary.
The end point of this analysis was the change in quality-adjusted life expectancy resulting from treatment, an outcome that allowed mortality and morbidity due to both the treatment and the underlying disease to be combined into a single outcome measure. In addition, we estimated the net marginal cost of intravenous immune globulin therapy (the cost of treating one additional patient) in this population. The cost effectiveness of treatment was then expressed as the ratio of the marginal cost of therapy to the gain in quality-adjusted life expectancy provided by intravenous immune globulin. The analysis has been structured to guide the clinician in determining which patients might benefit from therapy and to assist health insurers and policy makers in assessing the cost effectiveness of this treatment strategy in comparison with other options.
Methods
Structure of the Model
We constructed a decision-analysis model to compare two strategies: (1) treatment with intravenous immune globulin at a dose of 400 mg per kilogram of body weight every three weeks for one year and (2) no immune globulin therapy. Costs and benefits were assessed from a societal perspective, except that indirect costs (such as wages lost because of treatment) and indirect benefits (such as increased productivity among treated patients) were not considered. Health outcomes were measured in terms of gains in quality-adjusted life expectancy, with "utility" weights used to adjust life expectancy downward for decreases in the quality of life associated with a given clinical state. Utilities were based on physicians' assessments of the quality of life in the various health states experienced by patients. Net costs were defined as program expenditures less resulting savings on health care costs. Costs and benefits beyond the one-year treatment period were discounted at a rate of 5 percent. The SMLTREE software package" was used to construct the model and perform the analyses.
Data and Assumptions
The sources of the probabilities of clinical events, costs, and utilities used in the model are described below. These base-line estimates were used to produce initial predictions of the impact of intravenous immune globulin therapy on quality-adjusted life expectancy and of the cost effectiveness of treatment. In reporting the results of the model, we present sensitivity analyses to describe the effect on life expectancy and cost effectiveness of varying all measures of efficacy, cost, and utility, both individually and in combination.
Efficacy and Complications
Data on the efficacy of prophylactic immune globulin therapy were derived from results of the randomized Cooperative Group trial.1 In that study, 81 patients with chronic lymphocytic leukemia were randomly assigned to receive either therapy with intravenous immune globulin at a dose of 400 mg per kilogram or placebo every three weeks for a year. Patients with chronic lymphocytic leukemia were eligible if they had increased susceptibility to infection as defined by either an IgG level ≤50 percent of the lower limit of normal for the hospital laboratory or a history of one or more major or moderate infections. Episodes of bacterial infection were graded as major (life-threatening infections requiring parenteral antibacterial therapy, hospitalization, or both), moderate (infections requiring oral antibacterial therapy), or trivial (infections requiring no therapy or at most only symptomatic or topical therapy).1
A statistically significant difference in the number of bacterial infections occurred between the two groups; 23 infections were documented in the 41 treated patients, and 42 infections in the 40 controls. Although the differences in the rates of trivial and major infections did not reach statistical significance, the overall difference was significant, and the trend in each subgroup was in the same direction. Therefore, the proportions of major, moderate, and trivial infections observed in each group were used as the base-line probabilities of each grade of infection in our model (Table 1Table 1
Base-Line Estimates of the Efficacy of Intravenous Immune Globulin.). The frequency of bacterial infections among the 57 patients who completed a full year of therapy was used to calculate the base-line estimates of the probability of remaining infectionfree for each treatment group (Table 1). An estimate of the expected number of infections per patient in each arm of the model was calculated from the number of patients who had one, two, three, four, and five infections over a year of follow-up. The average number of infections per patient among those who had at least 1 bacterial infection was 1.40 in the treated group and 2.25 in the control group. On the basis of the types of infection observed in the Cooperative Group trial, we estimated the duration of trivial infections at 5 days and that of moderate infections at 10 days. Major infection was assumed to result in a 15-day hospitalization, somewhat longer than the 10-day average length of stay for persons 65 years and older with pneumonia,12 since most patients with chronic lymphocytic leukemia are not only elderly but also immunocompromised. Estimates of the efficacy of intravenous immune globulin and the duration of infection were examined in sensitivity analyses.There was no difference in mortality between the treated and untreated arms of the trial. The overall one-year mortality rate of 7.4 percent (6 deaths among 81 patients) served as the base-line probability of death in both groups; the number of deaths in the trial was too small to draw any meaningful conclusions about the effect of intravenous immune globulin treatment on the timing of deaths. In our model, therefore, it was assumed that these deaths occurred midway through the one-year follow-up period. Consequently, utilities and costs for patients who died from causes other than a fatal reaction to immune globulin therapy were set at half the value of those measures for comparable patients who survived to the end of the year. This assumption was examined in sensitivity analyses.
The reported frequency of adverse reactions to intravenous immune globulin in the Cooperative Group trial was 2 percent, which is consistent with adverse-reaction rates reported by others13; this served as our base-line probability of a reaction to intravenous immune globulin. It was assumed that all reactions occurred as a result of the first infusion in the treatment year and that patients who had a reaction received no further immune globulin therapy and thus had the same rates of infection as the untreated control group.
Costs
Costs of treatment, adverse reactions, and infections (in 1989 dollars) were derived from cost data (not data on charges) provided by two Boston teaching hospitals. Estimates of medical resources used were based on the authors' judgment and subjected to extensive sensitivity analyses to determine whether empirical measurement was necessary.
The cost of immune globulin in 1989 was approximately $30 per gram. The cost of a dose at 400 mg per kilogram, assuming an average body weight of 70 kg, was therefore estimated at $840. Assuming a preparation time of 30 to 45 minutes, the marginal cost of preparation was estimated to be $10 per dose. The duration of the infusions was reported to average 2.5 hours in the Cooperative Group study. The cost of administering an infusion was estimated at $60, on the basis of the cost of an outpatient transfusion. The total cost per dose of immune globulin was therefore $910, and the cost per year of therapy (17 doses) was $15,470.
Adverse reactions in the Cooperative Group trial were mild (for example, soreness at the injection site) and were therefore assumed to have no cost.
Estimates of the medical costs arising from infections were based on component costs (see the Appendix). The cost of a trivial infection was estimated at $44, that of a moderate infection at $189, and that of a major infection at $5,149.
Quality Adjustment
Utility estimates, used as weights in the calculation of quality-adjusted life expectancy, were obtained from a sample of 10 practicing oncologists experienced in the care of patients with chronic lymphocytic leukemia. In deriving these estimates, we used the reference-gamble approach,14 in which the respondent is asked to choose between life in a given clinical state and a gamble between death (assigned a value of 0) and perfect health (assigned a value of 1). The reference gamble elicits a measure of the respondent's assessment of the relative quality of life in that state, ranging from 0 to 1.
In our study, each of the 10 physicians was asked to assign a relative quality adjustment to one year of life in each of the following clinical states: chronic lymphocytic leukemia without bacterial infection; chronic lymphocytic leukemia with a trivial bacterial infection, such as folliculitis or a paronychia; chronic lymphocytic leukemia with a moderate bacterial infection, such as bronchitis or otitis, requiring oral antibiotic therapy; chronic lymphocytic leukemia with a life-threatening bacterial infection, such as pneumonia or septicemia, requiring parenteral antibiotics, hospitalization, or both; and chronic lymphocytic leukemia without bacterial infection but with a 2.5-hour outpatient intravenous infusion administered daily (Table 2Table 2
Relative Quality Adjustments for Clinical States.*). In the reference gambles, we provided no description of the symptoms associated with a diagnosis of chronic lymphocytic leukemia; however, the physicians were told that the probabilities of stage A, B, and C disease were 25, 35, and 40 percent, respectively, as in the study population.1 Studies of physicians' utility estimates have shown that they tend to be lower than patients' estimates but higher than those of the general public.15 , 16 There is no consensus on the best source of utilities for cost-effectiveness analyses; we therefore used physicians because their familiarity with the various manifestations of chronic lymphocytic leukemia allowed them to tailor their estimates to the spectrum of clinical stages represented in the Cooperative Group trial. In applying the results of this analysis to an individual patient, it would of course be appropriate to substitute that patient's preferences.The high, low, and mean quality-adjustment weights provided by the 10 physicians for each clinical state are shown in Table 2. For the base-line model, mean weights were used, except that the relative quality of the immune globulin-infusion days was set equal to the relative quality of life with chronic lymphocytic leukemia but without an infusion. In other words, no adjustment was made to reflect the inconvenience of treatment unless it was complicated by an adverse reaction. The implications of this assumption, as well as alternative formulations of the model, are discussed below.
The expected value of each outcome was set equal to the weighted sum of the component parts. For example, one year of life on intravenous immune globulin therapy without any bacterial infections was assigned a value equal to the sum of two products: the relative quality of a treatment day times the proportion of a year spent in treatment (17 days divided by 365 days), and the relative quality of life with chronic lymphocytic leukemia but without infection times the proportion of a year without treatment (348 days divided by 365 days). The impact of infection on the number of quality-adjusted life-years was incorporated by weighting the proportion of the year spent with an infection by the relative quality of life with each grade of infection.
Life Expectancy
Life expectancy was estimated by deriving a median length of survival for the group based on weighted survival probabilities according to disease stage.17 Using the distribution of stages in the Cooperative Group trial (25 percent in stage A, 35 percent in stage B, and 40 percent in stage C), the median survival was estimated to be 4.2 years, or an additional 3.2 years beyond the study year.
Results
Base-Line Estimates
With use of the base-line assumptions, according to which treatment was considered to entail no inconvenience, the model predicted that treating patients with chronic lymphocytic leukemia with prophylactic intravenous immune globulin for 1 year would produce an additional 0.0023 quality-adjusted life-year. In other words, treatment with intravenous immune globulin would result in 0.8 additional quality-adjusted day per patient per year of therapy. The marginal cost of treatment—that is, the additional cost of treating one patient less any savings on that patient's other health care costs—would be $13,984. Therefore, the cost-effectiveness ratio, measured as the additional cost of treating one patient divided by the resulting gain in quality-adjusted life expectancy, would be $6 million per quality-adjusted life-year.
Sensitivity Analyses
Does Therapy Benefit Patients?
If intravenous immune globulin infusions are assumed to entail no inconvenience, so that a day when the patient receives an infusion is no worse than a usual day without an infusion, immune globulin therapy results in only a very slight benefit, measured as a gain in quality-adjusted life expectancy, to treated patients. Under the assumption of no inconvenience, intravenous immune globulin treatment still increases quality-adjusted life expectancy as compared with no treatment even if estimated rates of infection and death are varied widely, as long as mortality in the treated group is not significantly higher than in the control group.
In contrast, if the inconvenience of receiving the intravenous infusion every three weeks is taken into account, treatment with immune globulin can result in a loss of quality-adjusted life expectancy. In other words, therapy can increase morbidity when the inconvenience of treatment is considered. Whether therapy results in a gain or loss of quality-adjusted life expectancy for a particular patient depends on that patient's relative utilities for the base-line state (chronic lymphocytic leukemia) and superimposed infection. Patients who tolerate infection poorly and are not bothered by the inconvenience of repeated infusions may benefit from treatment. However, such patients may be in the minority; only 3 of the 10 sets of utilities generated by the physicians resulted in a gain in quality-adjusted life expectancy due to intravenous immune globulin.
Is Treatment Cost Effective?
If the inconvenience of therapy is taken into account, treatment causes a loss of quality-adjusted life expectancy; it is therefore not cost effective and would not be used even if it were free. If a day on which intravenous immune globulin infusion is administered is no worse than a day without an infusion, the estimated cost-effectiveness ratio of intravenous immune globulin under the base-line assumptions is $6 million per quality-adjusted year of life. This estimate is quite sensitive to variations in assumptions about survival and quality adjustment but is minimally altered by wide variations in assumptions about costs. Specifically, 10-fold variations in the estimated costs of infection hardly change the cost-effectiveness ratio. If immune globulin and its preparation and administration have no cost, treatment results in a net savings of $814, because of lower infection rates and, thus, lower medical costs. At a cost of $50 per treatment, the marginal cost of treatment equals that of no treatment. Small increases in the cost of intravenous immune globulin result in large increases in the cost-effectiveness ratio. For example, even if the intravenous immune globulin itself were to cost as little as 25 percent of the current price, the cost-effectiveness ratio would be $ 1.6 million per quality-adjusted life-year.
Varying the estimates of the efficacy of immune globulin has only a small effect on cost effectiveness. This is not surprising since the reductions in utility associated with infection are small, the mortality rates in the two groups are equal, and the cost of therapy is high. Consequently, targeting therapy to a group of patients at very high risk for infection would not dramatically improve the cost-effectiveness ratio. For example, even if the infection rate among untreated patients were four times higher than the rate observed in the Cooperative Group trial and if treatment with intravenous immune globulin reduced the rates of infection to the low levels observed in the treated group in the trial (there was an eightfold reduction in infections in the treated group as compared with the untreated controls), the cost-effectiveness ratio would remain high, at $530,000 per quality-adjusted life-year.
The Cooperative Group trial did not demonstrate a statistically significant decrease in mortality at one year with intravenous immune globulin therapy. If a larger trial succeeded in showing a survival advantage, however, would treatment emerge as a cost-effective strategy? To answer this question, we modified our model to take long-term outcomes into account. Specifically, all patients surviving at the end of the 1-year study period were assigned an additional life expectancy (before discounting) of 3.2 years, the expected median length of survival of a cohort of patients with chronic lymphocytic leukemia comparable to those participating in the Cooperative Group trial. Despite this modification, even a dramatic decrease in mortality due to intravenous immune globulin treatment would not lower the cost-effectiveness ratio into a reasonable range. For example, if the mortality rate in the treated group during the one-year study period were reduced by 50 percent and if mortality without treatment were unchanged, the cost-effectiveness ratio would still remain high, at $1.3 million per quality-adjusted life-year.
Finally, we performed further analyses to determine whether a combination of reasonable assumptions could be identified that would result in a lower cost-effectiveness ratio for intravenous immune globulin treatment. Sensitivity analyses showed that all estimates would have to be varied in the direction most favorable to intravenous immune globulin and to a clinically unrealistic degree for this to occur. For example, the cost effectiveness of intravenous immune globulin could be reduced to $34,400 per quality-adjusted life-year if immune globulin therapy were assumed to produce a 50 percent reduction in one-year mortality, if treatment resulted in a probability of remaining infection-free that was 50 percent higher than the already high probability observed in the Cooperative Group trial, if quality weights for infection were 50 percent lower than the base-line estimates, and if the cost of intravenous immune globulin were 50 percent lower than the current cost. Less dramatic changes in any one of these variables would result in a higher cost-effectiveness ratio.
Discussion
We used data on the efficacy of intravenous immune globulin therapy in patients with chronic lymphocytic leukemia and hypogammaglobulinemia from a well-designed and carefully conducted randomized controlled trial to estimate the benefits to patients and the costs to society of this therapy. Our model demonstrated that a statistically significant decrease in the rate of bacterial infections might not produce improvement in the length or quality of treated patients' lives. Specifically, when the inconvenience of an uncomplicated 2.5-hour intravenous infusion every three weeks was incorporated into the model, treatment with immune globulin resulted in a loss of quality-adjusted life expectancy for most patients. If the morbidity due to the treatment itself was not considered, intravenous immune globulin therapy resulted in a slight increase in quality-adjusted life expectancy at a cost of approximately $6 million per quality-adjusted life-year. By comparison, costs in the range of $25,000 per quality-adjusted life-year associated with treatment of moderate hypertension,18 or $35,000 per year of useful life associated with renal dialysis,19 are widely believed to approximate the amount society is willing to pay for medical interventions.
If short courses of immune globulin replacement therapy resulted in prolonged protection against bacterial infection, the strategy would become more cost effective. Even though repeated therapy with intravenous immune globulin appears to prolong the half-life of infused immune globulin to several months,20 however, sustained protection after the cessation of therapy is unlikely. The dose of immune globulin used by the Cooperative Group was higher than the doses used in other studies.3 , 5 But as demonstrated by sensitivity analysis, even a marked reduction in the cost of immune globulin would not significantly improve the cost effectiveness of treatment. Infusion of immune globulin in the home has been used with some success in treating patients with agammaglobulinemia resulting from primary immunodeficiency states,21 and this approach might be considered as an option for selected patients with chronic lymphocytic leukemia. Although we found that the cost-effectiveness ratio was insensitive to a decrease in the cost of administering immune globulin, it was sensitive to quality adjustment. If home infusion resulted in a higher relative quality of life for days with immune globulin infusion, it could bring estimates of the cost-effectiveness ratio down, but only to the range of the base-line model estimate—that is, about $6 million per quality-adjusted life-year (Table 3Table 3
Effect of Intravenous Immune Globulin Treatment on Quality-Adjusted Life Expectancy and the Resulting Cost-Effectiveness Ratio.). Finally, sensitivity analysis demonstrated that even if a larger randomized trial succeeded in demonstrating a decrease in mortality with intravenous immune globulin, treatment would be unlikely to emerge as a cost-effective strategy. However, the one-year mortality rate in the Cooperative Group trial was low (7.4 percent), so that even a 50 percent reduction in mortality would not produce a large absolute gain in life-years. Consequently, if future trials are able to identify subgroups of patients with chronic lymphocytic leukemia who have much higher one-year mortality rates and to show dramatic reductions in mortality with intravenous immune globulin prophylaxis, then this could prove to be a cost-effective strategy for such patients.The potential cost of widespread use of intravenous immune globulin therapy in this population can be estimated from the prevalence of the disease. If half of all patients with chronic lymphocytic leukemia have hypogammaglobulinemia,22 and if the prevalence of the disease is roughly equal to the incidence (10,000 new cases annually in the United States)23 multiplied by the duration of the disease (six years24),25 then approximately 30,000 patients in the United States may be candidates for therapy at any time. At the marginal cost of $14,000 per patient predicted by the model, universal intravenous immune globulin therapy for patients with chronic lymphocytic leukemia and hypogammaglobulinemia would cost approximately $420 million per year, if one assumes no change in unit price with increased volume.
Our analysis does not consider the potential benefit of immune globulin replacement in reducing the rates of hemolytic anemia or platelet-transfusion requirements in patients with chronic lymphocytic leukemia.3 , 26 If future trials demonstrate an effect on these costly and morbid complications, replacement therapy may emerge as a more cost-effective strategy. Until either a substantial increase in life expectancy or a marked reduction in costs, or both, can be shown, intravenous immune globulin prophylaxis in chronic lymphocytic leukemia should be regarded as an extremely expensive therapy of unproved effectiveness.
This conclusion does not contradict the results of the Cooperative Group trial. The members of the group adhered to rigorous standards in designing, conducting, and reporting the trial, which clearly demonstrated that intravenous immune globulin produced a significant difference in an outcome of interest. But our analysis indicates that an intervention that results in a statistically significant change in a complication of a disease may not produce an overall benefit to patients at an acceptable cost. In deciding whether to adopt a new therapy in clinical practice, physicians must consider the inconvenience and morbidity caused by the treatment and the underlying disease as well as the magnitude of the clinical effect produced by the trial intervention. Decision-analysis techniques provide a method of assessing the combined effect of these factors on the well-being of the patient and of comparing the costs incurred with generally accepted norms. The application of these techniques may be especially useful in reporting the results of clinical trials that do not demonstrate a marked prolongation of life.
Supported in part by the Kellogg Program for Training in Research in Clinical Effectiveness.
We are indebted to Lee Goldman, M.D., and Robert J. Mayer, M.D., for their contributions.
Source Information
From the Division of Clinical Oncology, Dana–Farber Cancer Institute (J.C.W.);the Infectious Disease Unit, Massachusetts General Hospital (M.R.T.); and the Department of Health Policy and Management, Harvard School of Public Health (M.C.W.); all in Boston. Address reprint requests to Dr. Weeks at the Division of Cancer Epidemiology and Control, Dana–Farber Cancer Institute, 44 Binney St., Boston, MA 02115.
Appendix: Component Costs of Episodes of Infection
Trivial Infection
One visit to a physician ($44).
Moderate Infection
Two visits to a physician ($44 per visit); one urinalysis ($3); one urine culture ($6); one blood culture ($16); one sputum culture ($26); one complete blood count with differential cell count ($10); one chest film ($33); and a 10-day course of antibiotics—for example, trimethoprim–sulfamethoxazole ($7).
Major Infection
One visit to the emergency room ($86); 14 hospital days in a semiprivate room ($208 per day) and 1 day in the intensive care unit ($557 per day); daily physician's fees ($45 per day); 15 days of intravenous antibiotics—for example, ampicillin and tobramycin ($26 and $18 per day); two chest films ($33 per study); two blood cultures ($16 per set); one urine culture ($6); one urinalysis ($3); one sputum culture ($26); three complete blood counts with differential cell counts and platelet counts ($10 each); two chemistry profiles ($26 each); and a standard follow-up visit to a physician ($44).
- References
References
1
Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia
Full Text | Web of Science | Medline2
Griffiths
Web of Science | Medline3
Besa
CrossRef | Web of Science | Medline4
Bottino
Medline5
Boelart J, Van Hoof A, Willemarck G, Eyndelf C, Delire M, Louwagie A. Infection prevention by intravenous immunoglobulin in patients with myeloma and chronic leukemia. In: Program and abstracts of the 27th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, October 4–7, 1987. Washington, D.C.: American Society for Microbiology, 1987:264. abstract.
6
Berkman
Web of Science | Medline7
Morrell
CrossRef | Web of Science | Medline8
Bunch
Medline9
Silber R, Stahl R. Chronic lymphocytic leukemia and related diseases. In: Williams WJ, Beutler E, Erslev AJ, Lichtman MA, eds. Hematology. 4th ed. New York: McGraw-Hill, 1990:1005–24.
10
NIH Consensus Conference
CrossRef | Web of Science11
SMLTREE, version 2.9. Roslyn, N.Y.: James Hollenberg, 1989 (microcomputer software program).
12
National Center for Health Statistics. Inpatient utilization of short-stay hospitalization by diagnosis: United States, 1980. Vital and health statistics. Series 13. No. 74. Washington, D.C.: Government Printing Office, 1983. (DHHS publication no. (PHS) 83–1735.)
13
Pirofsky
CrossRef | MedlineErratum, Rev Infect Dis 1986; 9:232
14
Weinstein MC, Fineberg HV. Clinical decision analysis. Philadelphia: W.B. Saunders, 1980:184–227.
15
Boyd
CrossRef | Web of Science | Medline16
Froberg
CrossRef | Web of Science | Medline17
Rozman
Web of Science | Medline18
Weinstein
CrossRef | Web of Science | Medline19
Goldman L. Cost awareness in medicine. In: Wilson JD, Braunwald E, Isselbacher KJ, et al., eds. Harrison's principles of internal medicine. 12th ed. New York: McGraw-Hill, 1991:11–6.
20
Lever
Web of Science | Medline21
Chapel
Web of Science | Medline22
Chapel
Web of Science | Medline23
Foon
Web of Science | Medline24
Rai
Web of Science | Medline25
Freeman
Web of Science | Medline26
Besa
CrossRef | Web of Science | Medline
- Citing Articles (51)
Citing Articles
1
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CrossRef2
Joshua E. Howell, Alison M. Gulbis, Richard E. Champlin, Muzaffar H. Qazilbash. (2011) Retrospective analysis of weekly intravenous immunoglobulin prophylaxis versus intravenous immunoglobulin by IgG level monitoring in hematopoietic stem cell transplant recipients. American Journal of Hematologyn/a-n/a
CrossRef3
Pia Raanani, Anat Gafter-Gvili, Mical Paul, Isaac Ben-Bassat, Leonard Leibovici, Ofer Shpilberg. (2009) Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis. Leukemia & Lymphoma 50:5, 764-772
CrossRef4
Ann C. Wu, A. David Paltiel, Karen M. Kuntz, Scott T. Weiss, Anne L. Fuhlbrigge. (2007) Cost-effectiveness of omalizumab in adults with severe asthma: Results from the Asthma Policy Model. Journal of Allergy and Clinical Immunology 120:5, 1146-1152
CrossRef5
Mutiat Tolu Onigbanjo, Jordan S. Orange, Elena E. Perez, Kathleen E. Sullivan. (2007) Hypogammaglobulinemia in a pediatric tertiary care setting. Clinical Immunology 125:1, 52-59
CrossRef6
K. W. L. Yee, S. M. O'Brien. (2006) Chronic Lymphocytic Leukemia: Diagnosis and Treatment. Mayo Clinic Proceedings 81:8, 1105-1129
CrossRef7
Kamran Darabi, Omar Abdel-Wahab, Walter H. Dzik. (2006) Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion 46:5, 741-753
CrossRef8
Christopher A.K.Y. Chong, George Tomlinson, Lisa Chodirker, Nassi Figdor, Mark Uster, Gary Naglie, Murray D. Krahn. (2006) An unadjusted NNT was a moderately good predictor of health benefit. Journal of Clinical Epidemiology 59:3, 224-233
CrossRef9
R. John Looney, Jennifer Huggins. (2006) Use of intravenous immunoglobulin G (IVIG). Best Practice & Research Clinical Haematology 19:1, 3-25
CrossRef10
R.C. Vickery. 2005. Bronchial Asthma. .
CrossRef11
S. Jolles, W. A. C. Sewell, S. A. Misbah. (2005) Clinical uses of intravenous immunoglobulin. Clinical and Experimental Immunology 142:1, 1-11
CrossRef12
Roy H. Perlis, David A. Ganz, Jerry Avorn, Sebastian Schneeweiss, Robert J. Glynn, Jordan W. Smoller, Philip S. Wang. (2005) Pharmacogenetic Testing in the Clinical Management of Schizophrenia. Journal of Clinical Psychopharmacology 25:5, 427-434
CrossRef13
Jennifer M Stephens, Paola Gramegna, Benjamin Laskin, Marc F Botteman, Chris L Pashos. (2005) Chronic Lymphocytic Leukemia: Economic Burden and Quality of Life. American Journal of Therapeutics 12:5, 460-466
CrossRef14
Paul E Sax, Elena Losina, Milton C Weinstein, A David Paltiel, Sue J Goldie, Tammy M Muccio, April D Kimmel, Hong Zhang, Kenneth A Freedberg, Rochelle P Walensky. (2005) Cost-Effectiveness of Enfuvirtide in Treatment-Experienced Patients With Advanced HIV Disease. JAIDS Journal of Acquired Immune Deficiency Syndromes 39:1, 69-77
CrossRef15
John C. Hornberger, Jennie H. Best. (2005) Cost utility in the United States of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone for the treatment of elderly patients with diffuse large B-cell lymphoma. Cancer 103:8, 1644-1651
CrossRef16
S. Molica. (2005) Quality of life in chronic lymphocytic leukemia: A neglected issue. Leukemia & Lymphoma 46:12, 1709-1714
CrossRef17
Clive S. Zent, Neil E. Kay. (2004) Advances in the understanding of biology and prognosis in chronic lymphocytic leukemia. Current Oncology Reports 6:5, 348-354
CrossRef18
D. Oscier, C. Fegan, P. Hillmen, T. Illidge, S. Johnson, P. Maguire, E. Matutes, D. Milligan. (2004) Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. British Journal of Haematology 125:3, 294-317
CrossRef19
Irina Knezevic-Maramica, Margot S. Kruskall. (2003) Intravenous immune globulins: an update for clinicians. Transfusion 43:10, 1460-1480
CrossRef20
Manfred Hensel, Martin Kornacker, Sophie Yammeni, Gerlinde Egerer, Anthony D. Ho. (2003) Disease activity and pretreatment, rather than hypogammaglobulinaemia, are major risk factors for infectious complications in patients with chronic lymphocytic leukaemia. British Journal of Haematology 122:4, 600-606
CrossRef21
Alberto Redaelli, Jennifer M Stephens, Benjamin L Laskin, Chris L Pashos, Marc F Botteman. (2003) The burden and outcomes associated with four leukemias: AML, ALL, CLL and CML. Expert Review of Anticancer Therapy 3:3, 311-329
CrossRef22
Gerassimos A. Pangalis, Theodoros P. Vassilakopoulos, Maria N. Dimopoulou, Marina P. Siakantaris, Flora N. Kontopidou, Maria K. Angelopoulou. (2002) B-chronic lymphocytic leukemia: practical aspects. Hematological Oncology 20:3, 103-146
CrossRef23
John H. Ward. (2001) Autoimmunity in chronic lymphocytic leukemia. Current Treatment Options in Oncology 2:3, 253-257
CrossRef24
Vicki A Morrison. (2001) Update on prophylaxis and therapy of infection in patients with chronic lymphocytic leukemia. Expert Review of Anticancer Therapy 1:1, 84-90
CrossRef25
Gerlinde Egerer, Manfred Hensel, Anthony D. Ho. (2001) Infectious complications in chronic lymphoid malignancy. Current Treatment Options in Oncology 2:3, 237-244
CrossRef26
Daniel P. Wirt, Francis J. Giles, Martin M. Oken, Philippe Solal-Celigny, J. Robert Beck. (2001) Cost-Effectiveness of Interferon Alfa-2b Added to Chemotherapy for High-Tumor-Burden Follicular Non-Hodgkin's Lymphoma. Leukemia & Lymphoma 40:5-6, 565-579
CrossRef27
Terry J. Hamblin. (2001) Achieving Optimal Outcomes in Chronic Lymphocytic Leukaemia. Drugs 61:5, 593-611
CrossRef28
S Tsiodras, G Samonis, M J Keating, D P Kontoyiannis. (2000) Infection and immunity in chronic lymphocytic leukemia.. Mayo Clinic Proceedings 75:10, 1039-1054
CrossRef29
Nelson Kalil, Bruce D. Cheson. (2000) Management of Chronic Lymphocytic Leukaemia. Drugs & Aging 16:1, 9-27
CrossRef30
Katharine Johnston, Jackie Brown, Karen Gerard, Moira O'Hanlon, Alison Morton. (1998) Valuing temporary and chronic health states associated with breast screening. Social Science & Medicine 47:2, 213-222
CrossRef31
John D. Graham, Phaedra S. Corso, Jill M. Morris, Maria Segui-Gomez, Milton C. Weinstein. (1998) EVALUATING THE COST-EFFECTIVENESS OF CLINICAL AND PUBLIC HEALTH MEASURES*. Annual Review of Public Health 19:1, 125-152
CrossRef32
A Messori. (1997) A retrospective cost-effectiveness analysis of interferon as adjuvant therapy in high-risk resected cutaneous melanoma. European Journal of Cancer 33:9, 1373-1379
CrossRef33
E. RICHARD STIEHM. (1997) Human intravenous immunoglobulin in primary and secondary antibody deficiencies. The Pediatric Infectious Disease Journal 16:7, 696-707
CrossRef34
Martin L. Lee, PhD, CStat, Robert Peter Gale, MD, PhD, Peng Lee Yap, MD. (1997) USE OF INTRAVENOUS IMMUNOGLOBULIN TO PREVENT OR TREAT INFECTIONS IN PERSONS WITH IMMUNE DEFICIENCY. Annual Review of Medicine 48:1, 93-102
CrossRef35
John R. Wingard, Gerald J. Elfenbein. (1996) HOST IMMUNOLOGIC AUGMENTATION FOR THE CONTROL OF INFECTION. Infectious Disease Clinics of North America 10:2, 345-364
CrossRef36
H. Chapel, M. Dicato, H. Gamm, V. Brennan, F. Ries, C. Bunch, M. Lee. (1994) Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes. British Journal of Haematology 88:1, 209-212
CrossRef37
Leonie Snowdon, John Gibson, DougE. Joshua. (1994) Frequency of infection in plateau-phase multiple myeloma. The Lancet 344:8917, 262
CrossRef38
R.I. Schiff. (1994) Intravenous gammaglobulin: pharmacology, clinical uses and mechanisms of action. Pediatric Allergy and Immunology 5:2, 63-87
CrossRef39
Charles L. Bennett, Jack L. Armitage, Deborah Buchner, Subhash Gulati. (1994) Economic Analysis in Phase III Clinical Cancer Trials. Cancer Investigation 12:3, 336-342
CrossRef40
Yehuda L. Danon. (1994) Improvement of Host Defenses with Hemopoietic Growth Factors. Pediatric Hematology-Oncology 11:2, 125-127
CrossRef41
S Birch. (1993) Changing the problem to fit the solution: Johannesson and Weinstein's (mis) application of economics to real world problems. Journal of Health Economics 12:4, 469-476
CrossRef42
Wood, Alastair J.J., , Pizzo, Philip A.. (1993) Management of Fever in Patients with Cancer and Treatment-Induced Neutropenia. New England Journal of Medicine 328:18, 1323-1332
Full Text43
H. D. Banta. (1993) Quality of life 1. Pharmacy World & Science 15:2, 45-49
CrossRef44
S. P. Mulligan, D. Catovsky. (1993) The chronic B-cell leukaemias. Australian and New Zealand Journal of Medicine 23:1, 42-50
CrossRef45
Bruce E. Hillner, Thomas J. Smith, Christopher E. Desch. (1993) Assessing the cost effectiveness of adjuvant therapies in early breast cancer using a decision analysis model. Breast Cancer Research and Treatment 25:2, 97-105
CrossRef46
H. GRIFFITHS, J. LEA, C. BUNCH, M. LEE, H. CHAPEL. (1992) Predictors of infection in chronic lymphocytic leukaemia (CLL). Clinical & Experimental Immunology 89:3, 374-377
CrossRef47
A.A.M. Todd, P.L. Yap. (1992) Applications of intravenous immunoglobulin in haematology. Blood Reviews 6:2, 105-117
CrossRef48
Bruce E. Hillner, Thomas J. Smith. (1992) Should women with node-negative breast cancer receive adjuvant chemotherapy? — Insights from a decision analysis model. Breast Cancer Research and Treatment 23:1-2, 17-27
CrossRef49
(1992) G-CSF for Fever and Neutropenia Induced by Chemotherapy. New England Journal of Medicine 326:4, 269-270
Full Text50
(1992) Prophylactic Immune Globulin in Chronic Lymphocytic Leukemia. New England Journal of Medicine 326:2, 139-139
Full Text51
Stiehm, E. Richard, . (1991) New Uses for Intravenous Immune Globulin. New England Journal of Medicine 325:2, 123-125
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