|Year : 2012 | Volume
| Issue : 2 | Page : 96-101
Cost-effectiveness of postremission intensive chemotherapy in comparison with allogeneic stem-cell transplantation in adult Egyptian patients with acute myeloid leukemia
Essam A Hassan, Amal M El Afifi, Nermeen Adel Nabih, Walaa Ali ELSalakawy
Internal Medicine Department, Hematology and Bone Marrow Transplant Units, Ain Shams University, Cairo, Egypt
|Date of Submission||08-Feb-2011|
|Date of Acceptance||06-Jan-2012|
|Date of Web Publication||23-Jun-2014|
Walaa Ali ELSalakawy
16 abdellatif elfaham St. Menniat Elsereg, Alkhalaphawy, Shoubra, Cairo
Source of Support: None, Conflict of Interest: None
We assessed the cost-effectiveness of postremission high-dose arabinoside (HiDAC)-based chemotherapy in comparison with allogeneic stem-cell transplantation (alloSCT)-based therapy in adult Egyptian patients with acute myeloid leukemia at either an intermediate or a poor cytogenetic risk.
Patients and methods
Forty young patients at either an intermediate or a poor cytogenetic risk received postremission intensive therapy (20 HiDAC-based/20 alloSCT-based). We analyzed the overall survival, disease-free survival, and cost effectiveness in both groups.
Patients were followed up over a period of 60 months. The mean overall survival was 36.32 months for the HiDAC-based group, whereas it was 48.8 months in the alloSCT-based group. The mean disease-free survival was 24.8 months in the HiDAC-based group, whereas it was 51.5 months in the alloSCT-based group. The mean total cost in the HiDAC-based group was 51 300 Egyptian pounds (nearly US$9000), whereas it was 88 250 Egyptian pounds (nearly US$15 482) in the alloSCT-based group.
For the postremission therapy in young acute myeloid leukemia patients at either an intermediate or a poor cytogenetic risk, HiDAC-based chemotherapy is less costly and less effective, whereas alloSCT is more costly and more effective in maintaining patients in durable remission.
Keywords: acute myeloid leukemia, allogeneic stem-cell transplantation, cost effectiveness, high-dose Ara-C, survival
|How to cite this article:|
Hassan EA, El Afifi AM, Nabih NA, ELSalakawy WA. Cost-effectiveness of postremission intensive chemotherapy in comparison with allogeneic stem-cell transplantation in adult Egyptian patients with acute myeloid leukemia. Egypt J Haematol 2012;37:96-101
|How to cite this URL:|
Hassan EA, El Afifi AM, Nabih NA, ELSalakawy WA. Cost-effectiveness of postremission intensive chemotherapy in comparison with allogeneic stem-cell transplantation in adult Egyptian patients with acute myeloid leukemia. Egypt J Haematol [serial online] 2012 [cited 2019 Nov 17];37:96-101. Available from: http://www.ehj.eg.net/text.asp?2012/37/2/96/135062
| Introduction|| |
Although current treatment strategies and supportive care have improved, the prognosis of acute myeloid leukemia (AML) remains poor 1. Approximately 60–80% of younger adults with AML achieve complete remission (CR) with induction chemotherapy. However, only 30–40% of such patients are alive and disease free at 5 years 2.
Thus, postremission therapy is definitely required to achieve long-term, disease-free survival (DFS); the possible approaches include high-dose arabinoside (HiDAC) and allogeneic stem-cell transplantation (alloSCT) 3.
However, AML is an expensive disease to treat because of the prolonged hospital care and high-level technological medical intervention required. On the basis of the experience at our center, alloSCT is less costly in Egypt than that in other countries. This may be in favor of alloSCT as the postremission treatment of choice for Egyptian adults with AML.
We carried out this study to analyze the cost-effectiveness of HiDAC in comparison with alloSCT in adult Egyptian patients with AML belonging to the intermediate or the unfavorable cytogenetic risk category.
| Patients and methods|| |
This study was carried out on 40 adult AML patients admitted at the Hematology/Oncology Unit and Bone Marrow Transplant Unit, Ain Shams University Hospital (Cairo, Egypt).
All selected AML patients belonged to the intermediate or the unfavorable cytogenetic risk category according to the published criteria adopted by the Southwest Oncology Group 4. All patients received an induction regimen of a continuous intravenous infusion of cytarabine (200 mg/m2/day) for 7 days, with daunorubicin (45 mg/m2/day – bolus dose) given on the first 3 days of cytarabine therapy.
Bone marrow (BM) aspiration was performed 28 days after the start of treatment. CR was defined as a normal cellular BM with normal erythroid and myeloid elements and less than 5% myeloblasts 5.
Human leukocyte antigen (HLA) typing of patients had been performed in CR and their siblings 6. Accordingly, patients were stratified into two groups:
- Group A (HiDAC group): 20 patients lacking an HLA-identical sibling donor were assigned to receive intensive consolidation chemotherapy (high-dose cytarabine-based HiDAC). The HiDAC dose was 1–3 g/m2 every 12 h for up to 12 doses per cycle.
- The number of HiDAC cycles ranged from two to five cycles (median=4 cycles) and the total dose of Ara-C ranged from 12 to 42 mg/m2 (median 24 mg/m2).
- Group B (AlloSCT group): 20 patients with an HLA-identical sibling donor were assigned to receive an allogeneic peripheral blood stem cell transplant.
Sixteen patients were conditioned with fludarabine 30 mg/m2 and busulfan 1 mg/kg/6 h from days –6 to –3 7. The other four patients received fludarabine 30 mg/m2 from days –6 to –3, busulfan 2 mg/kg/6 h on day –2, and cyclophosphamide 60 mg/kg over 2 days (–6 and –4) as a conditioning regimen 8.
Graft-versus-host disease (GVHD) prophylaxis consisted of intravenous cyclosporine A (CsA) 3 mg/kg/day from day –2 and methotrexate 10 mg/m2 on days 1, 3, 6, and 11. The dose of CsA was modified according to the weekly plasma levels determined (200–400 ng/ml). Oral CsA was started once patients could swallow a dose of 5 mg/kg/day 9.
Neutrophil and platelet engraftment was defined as the first of 3 consecutive days on which the neutrophil and platelet counts exceeded 0.5×109 and 50×109/l, respectively 10. All patients received granulocyte colony-stimulating factor after chemotherapy or alloSCT. The patients from the two groups were followed up over a period of 60 months (May 2005–2010), with a mean of 22.3±15.9 months (range 2.2–60 months) following CR.
Total cost analysis
All patients were admitted in a regular single bedroom with a laminar airflow device. The cost analysis estimation included direct inpatient costs (room costs, pharmacy, blood bank, stem cell separation and infusion, laboratory tests, imaging procedures, and supportive care). Supportive care included control of GVHD, control of infection, blood transfusion, and terminal care.
Cost analysis did not include physician fees, outpatient costs, or patient time costs, productivity costs, and direct nonmedical costs. Payments of all hospitalizations were retrieved from the administrative database. All costs were estimated in Egyptian pounds and then converted into US$ (US$1=5.7 Egyptian pounds during this time period). The effectiveness end points were survival and durable CR.
The cost-effectiveness of each treatment modality was calculated by dividing the mean total cost of each treatment group by its mean survival. To calculate cost-effectiveness, the effects (mean survival time calculated using the Kaplan–Meier method) and the mean cost per patient for alloSCT and HiDAC were estimated initially. The presence of dominance (when one strategy is both less costly and more effective than the other) was assessed by comparing the estimates for the mean survival and the mean cost for each group. If no dominance was present, the cost-effectiveness of each treatment modality was calculated by dividing the mean total cost of each treatment group by its mean survival 11.
All analyses were carried out using the SPSS statistical package software version 13 (SPSS Inc., Chicago, Illinois, USA). Actuarial probability of survival was calculated using the method of Kaplan and Meier 12. Comparisons of the use of resources and costs were carried out using the Mann–Whitney test. A value of P less than 0.05 was considered statistically significant.
| Results|| |
Between May 2005 and 2010, 40 adult AML patients with a mean age of 31.8±10 years (range 16–54 years) were enrolled in this study. According to the availability of matched sibling donor, 20 patients received intensive consolidation chemotherapy (HiDAC group) whereas the remaining 20 patients received allogenic SCT (alloSCT group).
The clinical characteristics of the two groups are shown in [Table 1]. The initial laboratory data are shown in [Table 2]. There was no significant difference between the two groups in the initial characteristics or in the initial laboratory data. There was no significant difference in the distribution of standard risk factors between the two groups [Table 3].
|Table 3: Comparison of the two groups in terms of standard risk factors using the &khgr;2-test|
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In the HiDAC group, 18 patients had intermediate-risk cytogenetics (90%) whereas two patients only had poor-risk cytogenetics (10%). The intermediate-risk cytogenetics included trisomy 21 (n=4), trisomy 8 (n=2), and 12 patients with a normal karyotype whereas the two patients who had poor-risk cytogenetics had monosomy 7 and del 5q31. In the AlloSCT group, 15 patients had intermediate-risk cytogenetics (75%) whereas five had poor-risk cytogenetics (25%). The intermediate-risk patients included trisomy 21 (n=2), del 13q22 (n=1), and 12 patients with a normal karyotype. Poor cytogenetic risk included monosomy 7 (n=1), t(6; 9) (n=1), del 11q23 (n=1), and t(9; 22) (n=2). There was no significant difference between the two groups in the cytogenetic risk.
Clinical outcome in the two groups
There was a higher percentage of living cases at the end of the follow-up in the alloSCT group (80 vs. 55%) but the difference was not statistically significant [Table 4]. There was a higher mean overall survival (OS) in the alloSCT group; however, the difference was not significant statistically [Table 5]; [Figure 1].
|Table 4: Comparison of the two groups in terms of clinical outcome using the &khgr;2-test|
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|Table 5: Comparison of the two groups in terms of overall survival using the log-rank test (Kaplan–Meier product limit)|
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|Figure 1: Kaplan–Meier curve for overall survival (OS) of patients from the two groups. Time 0 indicates the time of achieving complete remission. The continuous line represents patients who received allogeneic stem-cell transplantation (alloSCT) as postremission therapy. The dashed line represents patients who received high-dose Ara-C (HiDAC) as postremission therapy.|
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However, there was a higher percentage of remitted cases in the alloSCT group at the end of the follow-up (80 vs. 35%) and the difference was highly statistically significant. In parallel, there was a higher mean DFS in the alloSCT group (P=0.02, significant) [Table 6]; [Figure 2].
|Table 6: Comparison of the two groups in terms of disease-free survival using the log-rank test (Kaplan–Meier product limit)|
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|Figure 2: Kaplan–Meier curve for disease-free survival (DFS) of patients from the two groups. Time 0 indicates the time of achieving complete remission. The continuous line represents patients who received allogeneic stem-cell transplantation (alloSCT) as postremission therapy. The dashed line represents patients who received high-dose Ara-C (HiDAC) as postremission therapy.|
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In the HiDAC group, 11 patients had BM relapse and two patients had a relapse of extra medullary disease (central nervous system and lung, N=1; nasopharyngeal mass, N=1), whereas in the AlloSCT group, two patients had a BM relapse and one patient had a relapse of extra medullary disease (ovarian mass).
On multivariate analysis, the treatment arm was found to affect DFS significantly, with a P value of 0.04 (i.e. AlloSCT produces a higher remission rate).
From the diagnosis to the end of the treatment, either cure or mortality, patients in the HiDAC group required a median of 66.55 days (13–165 days) of in-hospital care, whereas patients in the alloSCT group required a median of 61.8 days (27–124 days) of in-hospital care. The mean duration of stay in the hospital was similar in the two groups, with no statistically significant difference (P=0.9).
The mean OS was 36.32 months (3 years) in the HiDAC group, whereas it was 48.8 months (4.1 years) in the alloSCT group. The mean DFS was 24.8 months (2.1 years) in the HiDAC group, whereas it was 51.5 months (4.3 years) in the alloSCT group.
The mean total cost in the HiDAC group was 51 300 Egyptian pounds (range 24 000–90 000), whereas it was 88 250 Egyptian pounds (range 70 000–115 000) in the alloSCT group. This is equivalent to US$9000 (HiDAC group) and US$15 482 (alloSCT).
There is no dominance in the two groups. The HiDAC group was less costly and less effective and the alloSCT group was more costly and more effective.
In terms of OS, the calculated cost-effectiveness (CCE) was 17 100 Egyptian pounds (LE)/life year saved in the HiDAC group, whereas in the alloSCT group, CCE was 21 524 LE/life year saved. It is noteworthy that the HiDAC group was more cost effective than the alloSCT group in terms of OS.
In terms of DFS, CCE was 24 429 LE/life year saved in CR in the HiDAC group, whereas in the alloSCT group, CCE was 20 523 LE/life year saved in CR. It is noteworthy that the alloSCT group was more cost effective than the HiDAC group in maintaining patients in CR.
| Discussion|| |
HiDAC as a consolidation chemotherapy, first used in the 1980s and shown to be superior to standard dose cytarabine in 1994, improved survival in patients with AML during the 1990s 13. AlloSCT was first introduced into clinical practice in the late 1970s. Improvements in survival in patients who underwent alloSCT have been documented owing to the improvements in immunosuppressive medications and supportive care techniques, including less toxic conditioning regimens, better treatment of and prophylaxis against GVHD, and better treatment of infections in neutropenic patients 3.
In this study, 40 adult Egyptian AML patients with a mean age of 31.8±10 years (range 16–54 years) were enrolled. They belonged to the intermediate or an unfavorable cytogenetic risk category. They were stratified into two groups according to the availability of the donor and the postremission treatment received. Twenty patients received HiDAC-based consolidation chemotherapy and the remaining 20 patients received peripheral blood alloSCT. There were no significant differences between the two groups in terms of the clinical and laboratory characteristics of the patients ([Table 1] and [Table 2]) or the distribution of standard risk factors ([Table 3]). This provided a homogenous distribution of clinical and laboratory characteristics as well as standard adverse prognostic factors in the two groups.
Many adverse prognostic factors affecting AML outcome have been reported in several studies 5,14–16.
In our study, the consolidation treatment arm administered was found to be an independent risk factor affecting OS and DFS, respectively, in multivariate analysis. In a study carried out by Junghanss et al. 17, the type of postremission treatment was found to significantly affect outcome in multivariate analysis, which is consistent with our results.
When we compared HiDAC and alloSCT groups for clinical outcome, there were higher cases of remissions, fewer relapses, and a statistically significant longer DFS in favor of alloSCT ([Table 5] and [Table 6], [Figure 1] and [Figure 2]). This may be attributed to the graft-versus-leukemia effect known to be associated with alloSCT 18. This graft-versus-leukemia effect is believed to be significant in our study as we did not carry out T-cell depletion of the grafts. Our results are not in agreement with those of the studies performed by Harousseau et al. 19, Cassileth et al. 20, Slovak et al. 4, Tsimberidou et al. 21, and Schlenk et al. 22. Although DFS was lower in the HiDAC group than in the alloSCT group in the previous studies, the difference was not significant. It should be noted that comparisons between the two groups in the first four studies were made on an intention-to-treat basis. Moreover, the nonsignificant difference in DFS between both the groups can be attributed to the different methodologies and patient characteristics. Many patients who were assigned to receive intensive chemotherapy in the study of Harousseau et al. 19 eventually received AlloSCT, which might have improved their outcome, in addition to the unexplained high relapse rate in the alloSCT group. Cassileth et al. 20 attributed the relatively low DFS in the alloSCT group to the delays in performing transplantation after achievement of CR. In addition, the intermediate risk category only included patients who had the normal karyotype. In the study performed by Slovak et al. 4, the AlloSCT treatment arm was included in the comparison. The smaller number of enrolled patients (N=15 in both groups) may explain the nonsignificant difference in DFS between the HiDAC and the AlloSCT groups in the study of Tsimberidou et al. 21. Finally, in the study of Schlenk et al. 22, all included patients were classified as follow: low risk: t(8;21) or inv/t(16q22); intermediate risk: normal karyotype; high risk: all other chromosomal abnormalities.
In a study carried out by Brunet et al. 16, DFS in the two groups was almost equal. This can be attributed to the fact that the HiDAC group included only patients with favorable risk cytogenetics whereas the alloSCT group included patients with intermediate and unfavorable risk cytogenetics. Also, ∼67% of the patients in the alloSCT group who relapsed had initially received T-cell-depleted grafts.
In our study, 45 and 15% of the patients in the HiDAC and the AlloSCT groups, respectively, died because of relapse. This is in agreement with the results of the study of Harousseau et al. 19.
In our study, although OS was lower in the HiDAC group than in the alloSCT group, the difference was not significant statistically ([Table 5]; [Figure 1]). Our results are in agreement with those of Zittoun et al. 23. Slovak et al. 4, and Tsimberidou et al. 21.
However, our results are not in agreement with those of Cassileth et al. 20 and Brunet et al. 16 as OS was higher in the intensive chemotherapy group than in the alloSCT group. This can be attributed to the higher treatment related mortality reported in the alloSCT group, the use of more toxic conditioning regimens, and the larger number of enrolled patients in comparison with our study. Moreover, in the study of Brunet et al. 16, ∼71% of the patients in the alloSCT group who died had initially received T-cell-depleted grafts, which translated into a high mortality rate because of relapse.
It should be noted from our results that although AlloSCT treatment resulted in a better DFS than HiDAC consolidation chemotherapy, this has not been translated into a significantly better OS in the AlloSCT group. The same has been observed in the studies of Cornelissen et al. 24 and Sakamaki et al. 25.
In terms of cost and cost-effectiveness, HiDAC chemotherapy was less costly than alloSCT in our study. The mean treatment cost for the HiDAC group in our study was low when compared with that reported by Welch and Larson 26 (US$136 000); Dufoir et al. 27 (US$23 726); and Yu et al. 11 (US$51 857). Also, the mean treatment cost for the AlloSCT group in our study was less than that reported by the above-mentioned studies (US$193 000, US$72 261, and US$75 474, respectively). The lower treatment cost of our AML patients was mainly because of the marked decrease in the room fee.
When we compared the cost drivers of both treatment strategies, we found that the lower total cost in the HiDAC-based group than the alloSCT group was because of a lower total room fee, medication and laboratory test cost, but not blood transfusion and imaging procedure costs. Blood bank costs were the largest cost driver for the chemotherapy patients in the study of Dufoir et al. 27, followed by medical staff costs, whereas for transplantation patients, it was medico technical treatments (because of total body irradiation and more biological testing such as virus isolation), followed by blood bank costs.
The number of days spent in the hospital was not a major cost driver in our study. The higher cost in the alloSCT group in the study of Welch and Larson 26 was attributed to the more frequent ICU admissions because of more frequent complications such as GVHD or cytomegalovirus infection. The reduced total cost in the HiDAC-based group in the study of Yu et al. 11 was because of the lower hospital days and the lower cost for medication, laboratory tests, and procedures.
In terms of hospital stay, there was no statistically significant difference between both the groups. In contrast, Dufoir et al. 27 reported a significantly higher mean number of hospitalization days in the alloSCT group than that in the chemotherapy group. The relatively high mean of hospital days in the HiDAC group in our study can be attributed to the high incidence of septicemia in this group, which in turn necessitated prolonged hospitalization.
We found that HiDAC chemotherapy was more cost-effective in terms of keeping the patients alive. This is consistent with the results of Dufoir et al. 27 and Yu et al. 11. In contrast, alloSCT was more cost-effective in the study of Welch and Larson 26. However, it should be noted that AlloSCT was more cost-effective in terms of maintaining the patients in durable CR in our study.
In conclusion, for the postremission therapy in young Egyptian AML patients at either an intermediate or a poor cytogenetic risk, HiDAC-based chemotherapy is less costly and less effective whereas alloSCT is more costly and more effective in maintaining patients in durable remission.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]