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1 October 1996 | Volume 125 Issue 7 | Pages 541-548
Objective: To compare the cost-effectiveness of interferon-
Design: A decision analysis and Markov model that described the natural history of the therapeutic process. The Markov model contained two treatment arms (interferon-
Measurement: Quality-adjusted years of life saved and costs and qualities discounted at 5% per year.
Setting: University medical centers in North America and Europe.
Patients: Meta-analysis of results from patients studied in clinical trials.
Results: The model's predictions of median survival (69 months with interferon-
Conclusion: Compared with hydroxyurea, interferon-
Conventional chemotherapy with hydroxyurea is inexpensive, is taken orally, and has few long-term side effects [2]. It confers a median survival of 41 to 58 months but is not associated with long-term survival in most patients; it also cannot cure CML [2-4]. In patients with CML, interferon-
Thus, the problem of initial therapy for chronic-phase CML is that conventional therapy offers little chance of long-term survival and no chance of cure, whereas an agent that offers superior survival and a chance of cure is toxic and expensive. We used a decision analysis model to compare the cost-effectiveness of interferon-
On the basis of data from recent large clinical studies [2, 3, 5, 6], we developed a model of the evolution of CML for which either hydroxyurea or interferon-
The Italian Cooperative Study Group on Chronic Myeloid Leukemia [3, 8] compared interferon-
On the basis of data on evaluable patients obtained in the Italian study during the first 24 months of therapy [8], we estimated that 12 patients could not tolerate interferon-
The Cancer and Leukemia Group B [5] reported a median survival of 66 months in 107 previously untreated patients with chronic-phase CML who received interferon-
Kantarjian and colleagues [6] recently reported their findings on 274 patients with chronic-phase CML who were treated with interferon-
Decision Analysis Model
We developed a decision analysis model [10] that was based on the probabilities of the clinical events detailed above. The model follows the decision tree structure for the first 8 months of front-line therapy (Figure 1). Our literature review suggested that the transition probabilities for remission and relapse within the first 8 months are different from those in subsequent months [3, 8]. The choice is between initial therapy with interferon-ARTICLE
Cost-Effectiveness of Interferon-
and Conventional Chemotherapy in Chronic Myelogenous Leukemia
with that of hydroxyurea as initial therapy for patients with chronic myelogenous leukemia (CML) in the chronic phase. and hydroxyurea) and eight states of health (complete hematologic remission with cytogenetic response, complete hematologic remission without cytogenetic response, partial hematologic remission, chronic phase without hematologic remission, accelerated phase, blast crisis, bone marrow transplantation, and death). Probabilities, costs, and utilities were obtained from published clinical studies and clinical investigators. therapy and 58 months with hydroxyurea therapy) were derived from data in the recent literature. In patients 50 years of age, interferon- improved life expectancy over hydroxyurea by approximately 18 months. The marginal cost-effectiveness of interferon- (incremental discounted cost of interferon- compared with that of conventional therapy) was $34 800 per quality-adjusted year of life saved. The model was sensitive to the monthly cost of interferon- therapy (if the cost of interferon- is reduced by one third, the cost-effectiveness becomes $19 300 per quality-adjusted year of life saved) but was not particularly sensitive to the costs associated with blast crisis or bone marrow transplantation. The other significant variable was quality of life during therapy with interferon-; when this measure was varied from 70% to 100% of the quality of life during hydroxyurea therapy, cost-effectiveness changed from $123 200 to $25 620 per quality-adjusted year of life saved. When the quality of life associated with interferon- was less than 62% of the quality of life associated with hydroxyurea, the discounted quality-adjusted life expectancy with interferon- was less than that with hydroxyurea. is, in most clinical scenarios, a cost-effective initial therapy for patients with chronic-phase CML who can tolerate the drug.
Chronic myelogenous leukemia (CML) usually presents in a chronic phase of variable duration, after which a fatal condition similar to acute leukemia (blast crisis) develops. In some patients, a transitional or accelerated phase is evident [1]. The Philadelphia (Ph) balanced chromosomal translocation, t(9:22)(q34; q11), is present in most malignant cells at the time of CML diagnosis [1]. Although allogeneic bone marrow transplantation is the preferred therapy in patients for whom a compatible donor is available, the current front-line options for most patients are hydroxyurea or interferon- [2-5]. Both drugs can engender a complete hematologic response, defined as a reduction in the marrow myeloblast count to less than 1% of the leukocytes and return of the peripheral blood leukocyte count to normal. therapy leads to a median survival that is somewhat longer (61 to 89 months) than that produced by hydroxyurea [3-5]. It also provides some patients with long-term survival, particularly patients who have a major karyotypic response (a substantial reduction in the number of Ph-positive marrow cells) [3, 6]. Interferon- is expensive, must be taken subcutaneously, and is associated with substantial toxicity in some patients. Approximately 20% of patients must discontinue therapy because of adverse side effects [3]. Those who continue to receive interferon- have reactions that range from mild to moderately severe. Interferon- may cure CML in some patients who have prolonged complete karyotypic response (no detectable Ph-positive marrow cells) [7]. with that of hydroxyurea as an initial strategy for chronic-phase, Ph-positive CML.
Methods
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Methods
Results
Discussion
Author & Article Info
References
Data Review is used as front-line therapy. With the help of experienced clinical investigators, we thoroughly dissected the data that underlie our decision analytic model. Conventional chemotherapy for CML has historically consisted of either hydroxyurea or busulphan. The German CML Study Group [2] recently reported results of a randomized comparison between hydroxyurea and busulphan as front-line therapy for chronic-phase CML. Hydroxyurea was clearly superior, conferring a median survival of 58 months. In contrast, busulphan was associated with a median survival of 45 months [2]. therapy (218 patients) with conventional chemotherapy (104 patients) in a randomized study. At 8 months, 64 patients receiving interferon- had complete hematologic remission. Of these 64 patients, 29 achieved a major karyotypic response [8]. Seventeen patients who received conventional therapy had complete hematologic remission; only 1 of these patients had a major karyotypic response. Partial hematologic responses were noted in 102 interferon- recipients and 68 hydroxyurea recipients. Thirteen patients (11 receiving interferon- and 2 receiving conventional chemotherapy) had no response to treatment. Progressive disease developed in 18 patients (12 receiving interferon- and 6 receiving conventional therapy). therapy during this period. An additional 28 patients could not be evaluated for hematologic response [8]; further review by the Italian group, however, indicated that about half of these patients subsequently had allogeneic bone marrow transplantation [3]. Karyotypic response occurred in 30% of patients receiving interferon- and in 5% of patients receiving conventional chemotherapy [3]. At 72 months, overall survival was 50% in the interferon- group and 30% in the chemotherapy group [3]. therapy. Twenty-nine percent of these patients (95% CI, 20% to 38%) had a major karyotypic response; the median time to karyotypic response was 9 months. for 10 years. Eighty percent of these patients had complete hematologic remission, and 38% had a major karyotypic response; 5-year survival rates ranged from 70% to 93% depending on the degree of karyotypic response. A recent analysis of 242 patients with CML blast crisis documented a median survival of 18 weeks [9]. or with hydroxyurea. For each branch of the decision node, the model is divided into the following possible states of health, depending on events that occur in the first 8 months of therapy:
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1. Complete hematologic remission with accompanying karyotypic response (a karyotypic response cannot be achieved with hydroxyurea);
2. Complete hematologic remission without accompanying karyotypic response;
3. Partial hematologic remission;
4. Chronic-phase CML without hematologic remission;
5. Accelerated-phase CML, characterized by increasing peripheral leukocyte counts and marrow blast counts;
6. Blast crisis of CML (>30% blasts in the marrow), which leads to an acute leukemic state;
7. Discontinuation of primary therapy and attempted allogeneic bone marrow transplantation because a donor became available; and
8. Death from CML or other causes.
The clinical research panel ratified the choice of states, but some of the reports on which the model is based use other states of health. In particular, the panel believed that "partial" karyotypic responses were difficult to judge, and they defined complete hematologic remission with karyotypic response as a 66% reduction (from the percentage of Ph-positive cells before treatment) in the proportion of Ph-positive metaphases in the bone marrow. Similarly, the panel judged that the natural history of partial hematologic response is similar (regardless of the changes in bone marrow after interferon- therapy) and therefore did not subdivide partial hematologic response into states with and without karyotypic response.
Except for the state of complete remission with karyotypic response, the initial states are duplicated in the computer model to reflect the natural history of CML with interferon- or hydroxyurea treatment. Interferon- is associated with a risk for clinically significant toxicity, which might necessitate a change of therapy in the first 8 months. The model assumes that therapy would be switched to hydroxyurea in month 4 (halfway through the initial treatment period). This simplification does not change the behavior of the model and keeps the tree from becoming computationally intractable.
Beginning with the ninth month of therapy, the natural history is modeled as a Markov process. We switched to a Markov model at month 9 because the transitions between states of health are relatively constant after this point. Figure 2 shows a diagram of the state-transition model. Because remissions still occur even after the eighth month of therapy, transitions to partial hematologic remission, complete hematologic remission with karyotypic response, and complete hematologic remission without karyotypic response are allowed. To overcome the limitation imposed by sparse data, patients with remission failure remain in their remission state until they progress to the accelerated phase rather than moving into the transient chronic state. The chronic-phase state and the remission states compete with a risk for progression to the accelerated phase. From any state that does not include karyotypic response or accelerated disease, a patient can discontinue primary therapy and have bone marrow transplantation. However, once disease is in the accelerated phase, the only forward transition is to blast crisis or death. Transition to death can occur from any state. To allow comparative analyses, death was subdivided into death from CML and death from other causes.
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Figure 3 shows other aspects of this Markov process for a patient who initially receives interferon-. At any time through month 24, toxicity can force a change to hydroxyurea. On the basis of discussions with the panel, interferon- treatment is discontinued at month 24 if no karyotypic response has been achieved. Therefore, patients who do not have complete hematologic remission at 24 months but do have accompanying karyotypic response are automatically switched to their corresponding hydroxyurea states by a Boolean Markov node [10].
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As with most Markov cohort studies, this computer model is run until an entire simulated population of patients has died. Death may occur because of disease, complications developing after bone marrow transplantation, or other factors.
Probabilities
Table 1 [11, 12] contains a list of transition probabilities used in the model. These probabilities were obtained from published reports, and their interactions were carefully assessed to replicate the results from recent clinical trials. Transition probabilities are calculated from the survival rates of cohorts according to the following formulas: P = S1/t, where P is the transition probability, S is the stated disease-free or remission-free survival, and t is the time point for analysis in years. Although the remission experience of several contemporary trials and the acceleration of CML from each state of health cannot be modeled exactly, Table 2 shows the fidelity of the model to results of major trials. This fidelity represents the closest agreement that could be achieved without overfitting the probability model or altering the clinical states.
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Costs and Utilities
The costs Table 3 referred to in the model are those for drugs or procedures as listed in a clinical-cost accounting system. These costs were obtained from three major U.S. cancer centers and two major European cancer centers. The cost of interferon- therapy, based on an average induction dose of 5 million U/m2 body surface area per day, was $1500 per month. After complete hematologic response, the drug is given only three times a week. Other diagnostic procedures that are done because of interferon- therapy, such as regular aspiration of bone marrow, add $100 per month to the cost of this regimen. Hydroxyurea therapy, 30 mg/kg of body weight per day, cost $163 per month. The cost of interferon- ranged from $500 per month for the maintenance dose to $2000 per month for the maximum induction dose. The cost of hydroxyurea ranged from $66 per month for the maintenance dose to $200 per month for the maximum dose. Intensified treatment of accelerated-phase CML cost $10 000 per month; this cost increased to $20 000 per month during the first 4 months of blast crisis and decreased to $5000 per month thereafter. Data from U.S. and European facilities indicated that costs after bone marrow transplantation are $150 000 for the first 6 months, $500 per month for the next 6 months, and then $500 per year. Costs of therapy for relapse after bone marrow transplantation or repeated transplantation were not built into the model. Intolerance to interferon- does not engender additional costs because such patients switch to hydroxyurea.
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Health states in the model are associated with differences in the perceived quality of life. The clinical panel met on two occasions to consider the utilities of the health states. These utilities are the quality-of-life indicators, in which 0 represents death and 1 represents perfect health. The panel was presented with scenarios that described the possible health states and assigned quality adjustments by direct scaling. Patients with CML who received hydroxyurea therapy were assigned a value of 1, regardless of remission status, because that value represents the highest possible quality of life given the diagnosis of CML. For patients who could tolerate interferon-, the utility associated with this drug varied from 0.6 to 1.0, with a baseline of 0.9. This baseline utility is similar to the 0.93 assigned to interferon- therapy in a recent cost-effectiveness model of chronic hepatitis B (dosing for this condition is similar to that for CML) [13]. In the Markov model, a month in the accelerated phase of CML or blast crisis was valued at 0.5 months, the first month after bone marrow transplantation was valued at 0, and the patient's status after bone marrow transplantation was set at 0.95. For consistency, these values were compared with quality adjustments from other published cost-effectiveness analyses of interferon-, and the effects of these values were compared with the effects seen in recent clinical studies that tracked dose-limiting interferon- toxicity [13-15].
Costs and quality-adjusted survival were each discounted at 0.05 per year to reflect the current best practices for cost-effectiveness analyses.
Results
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therapy and 58 months with hydroxyurea therapy. These durations are similar to those recently reported by the cooperative trial groups. Median survivals with interferon- were 89 months in the study by Kantarjian and colleagues [6], 72 months in the Italian CML trial [3], and 66 months in the Cancer and Leukemia Group B trial [5]. Median survivals with hydroxyurea were 56 months in the Italian CML trial [3] and 58 months in the German CML trial [2].
In our study, life expectancy was 91 months with interferon- and 73 months with hydroxyurea. The large disparity between median survival and life expectancy is characteristic of CML, which has censored results and a tail of longer-term survivors [16]. Life expectancy, or mean survival, is the basis of the Markov model. During the course of the model, 25% of the patients who originally received interferon- were switched to hydroxyurea because of toxicity. This Figure is similar to that described in recent studies [15].
Because of its toxicity and delayed and immediate costs, interferon- therapy engendered a discounted average lifetime expenditure per 50-year-old patient of $118 000; the expenditure for hydroxyurea therapy was $93 900. The marginal cost-effectiveness, defined as the difference in costs divided by the difference in discounted expected survival, was $26 500 per year of life saved. When adjusted for perceived states of health, the cost-effectiveness increased to $34 800 per quality-adjusted year of life.
The top panel of Figure 4 shows the marginal cost-effectiveness of interferon- therapy as a function of patient age at diagnosis, from 30 to 70 years of age. Therapy with interferon- was most cost-effective when patients were 30 years of age ($30 830 per quality-adjusted year of life); by 70 years of age, the cost-effectiveness was $61 200.
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The model was relatively sensitive to the monthly cost of interferon- (Figure 4, middle). If the cost of interferon- were reduced to $1000 per month and all other costs remained constant, the marginal cost per quality-adjusted year of life would decrease to $19 270. However, the model was not particularly sensitive to the costs associated with blast crisis, bone marrow transplantation, and maintenance after bone marrow transplantation. The chance of progressing to blast crisis was greater in patients receiving hydroxyurea; thus, the higher the cost associated with blast crisis, the "better" the cost-effectiveness of interferon-.
Similarly, more patients receiving hydroxyurea were switched to bone marrow transplantation. If bone marrow transplantation were half as costly as reports from the clinical centers in our study indicated, the marginal cost per quality-adjusted year of life associated with interferon- would increase slightly, to $35 800. As occurred with the cost of blast crisis, interferon- became more cost-effective when the cost of maintenance therapy after bone marrow transplantation increased.
One important question about utility is the degree to which interferon- therapy interferes with perceived quality of life. The bottom panel of Figure 4 shows the effect of varying the quality of life for a patient treated with interferon- from 100% (no different than with hydroxyurea) to 62% (as bad as with severe angina or equivalent to the quality of life with the most severe side effects of medication reported in the literature [12]). At a baseline quality adjustment of 90%, the marginal cost per quality-adjusted year of life with interferon- was $34 800. If interferon- does not decrease quality of life, as is true for some patients, the cost-effectiveness improved to $25 600 per quality-adjusted year of life. At a quality reduction of 38% (the percentage seen if a day of interferon- therapy has 62% of the quality of life of a day of hydroxyurea therapy), the quality-adjusted life expectancy with both therapies is equal. Thus, the marginal cost-effectiveness of interferon- is essentially undefined. If the quality of life with interferon- is worse than 62% of that with conventional chemotherapy, hydroxyurea becomes less costly and more effective than interferon-.
In a related sensitivity analysis, the fraction of patients forced to switch from interferon- to hydroxyurea because of toxicity varied. If the proportion of patients with treatment-limiting toxicity increases from 25% to 45%, as was seen in a recent clinical trial of interferon- in multiple myeloma [14], the cost-effectiveness of interferon- at baseline quality adjustments increases from $34 800 to $35 900 per quality-adjusted year of life.
Discussion
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has been clearly shown to prolong survival [3, 4], but the drug is more expensive and toxic than the alternate conventional agent, hydroxyurea. We developed a hybrid decision analysis and Markov model for the natural history of the alternate therapeutic agents; we could then compare the cost-effectiveness of interferon- with that of hydroxyurea as front-line therapy for chronic-phase CML. The model allowed us to systemically investigate several variables that govern the cost-effectiveness of these therapies. Survival (measured by life expectancy) is higher with interferon- than with hydroxyurea. The model considers quality-of-life modifiers in survival calculations. Quality-adjusted survival remained significantly higher with interferon-, even when the toxicity of the drug was considered.
The model is driven by the cost of interferon-. This measure, when varied in a sensitivity analysis, had the greatest effect on the marginal cost-effectiveness of interferon-. Still, even at the maximum cost in the range considered here, the marginal cost-effectiveness is similar to that of many standard treatments [16-24] (Table 4). The clinical panel judged the cost of complications resulting from interferon- to be minimal.
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The effect of interferon- on quality of life can be substantial. At reported rates of dose-limiting toxicity and a 10% quality-of-life adjustment for patients who continue to receive interferon-, the treatment is clearly cost-effective. If the quality-of-life adjustment worsens to 38%, the quality-adjusted life expectancy associated with interferon- is less than that with conventional chemotherapy. However, this value is implausible. As the model is constructed, this would mean that the average quality of life for patients receiving interferon- is 62% of the average quality of life for patients receiving hydroxyurea but that the patients still continue to receive the toxic treatment. Much more likely would be an increase in the patient drop-out rate over the 25% seen in the baseline model. Because patients drop out over time, and because patients continuing to receive interferon- presumably enjoy a better functional health status than patients forced to withdraw, the effect of increased drop-out is less than that of directly reduced quality. Nevertheless, each patient has a different experience, and patient preference should play an important role in treatment decisions.
Schofield and colleagues [25] recently suggested that low-dose interferon-, which has minimal toxicity, may be as effective as standard-dose interferon- in prolonging survival in chronic-phase CML. These investigators reported that interferon- costs $500 per month; this cost is shown at the left-hand edge of the middle panel of Figure 4. Equivalent clinical efficacy at reduced doses of interferon- would allow a considerable reduction in cost and toxicity. At the doses reported by Schofield and colleagues, the marginal cost-effectiveness of interferon- therapy improves to $3700 per quality-adjusted year of life. However, most clinical data to date suggest that in CML, the interferon- dose is associated with the response to treatment; further data on the effects of low-dose interferon- regimens are required.
Our analysis has several limitations. It is based on clinical and cost data from leading academic centers, where the intensity of CML treatment is maximal and the results appear to be better than those in other settings. These results may not be directly applicable to other clinical settings. The statistical variance of our results is high, but this is a limitation of all Markov cost-effectiveness analyses [10]. Sensitivity analyses show that, at least for patients younger than 70 years of age, the cost-effectiveness of interferon- therapy is reasonable.
Utilities (quality adjustments) were derived from an expert panel and not from actual patients with CML. Patient data are now being collected in new clinical trials that are using standard measures of quality of life [26]. The quality adjustments used in our model are similar to those used in other studies of interferon- [13], and the 10% baseline penalty for interferon- is relatively severe for a drug that is well tolerated, except in patients for whom toxicity forces a change of therapy. Still, actual patient experiences will improve the reliability of this model.
In conclusion, we evaluated the cost-effectiveness of interferon- and hydroxyurea therapy for chronic-phase CML over a wide range of conditions. Our results suggest that under plausible conditions, interferon- is a cost-effective front-line therapy compared with conventional chemotherapy. In our analysis, the cost and necessary dose of interferon- and quality-of-life adjustment for patients receiving interferon- were significant variables. The relative values of interferon- and bone marrow transplantation in the patients for whom the latter is an option must still be established by appropriate randomized studies.
From Baylor College of Medicine and University of Texas M.D. Anderson Cancer Center, Houston, Texas; Yamaguchi University School of Medicine, Yamaguchi, Japan; Cedars-Sinai Medical Center, Los Angeles, California; Emory University School of Medicine Cancer Center, Atlanta, Georgia; Centre Hospitalier Regional et Universitaire La Miletrie, Poitiers, France; and University of Bologna, Bologna, Italy.
Dr. Inoue: Department of Medical Informatics, Yamaguchi University School of Medicine, 1144 Kogushi, 7, Yamaguchi 755, Japan.
Dr. Giles: Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Becker B-209, Los Angeles, CA 90048.
Dr. Talpaz: M.D. Anderson Cancer Center, Box 302, 1515 Holcombe Boulevard, Houston, TX 77030.
Dr. Ozer: Emory University School of Medicine Cancer Center, 1365 Clifton Road, Suite B4100, Atlanta, GA 30322.
Dr. Guilhot: Department of Hematology, Center Hospitalier Regional et Universitaire La Miletrie, BP577, Poiters 86201, France.
Dr. Zuffa: Institute of Hematology, Policlinico S. Orsola, University of Bologna, via Massarenti 9, 40138 Bologna, Italy.
Mr. Huber: M.D. Anderson Cancer Center, Box 706, 1515 Holcombe Boulevard, Houston, TX 77030.
Author and Article Information
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References
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