Technical Appendix to Economic evaluation of plerixafor for stem cell mobilization in people with non-Hodgkins Lymphoma The purpose of this appendix is to provide technical detail regarding the model used in our paper, as suggested by The Panel on Cost-Effectiveness in Health and Medicine. 1 For the reader familiar with these methods, this information should provide sufficient information to replicate our results given the same data. Other readers should find this appendix useful for assessing the validity of our methods, evaluating the source of parameters used in the model, or how specific assumptions or methods were tested. If after reviewing this appendix important questions remain unanswered, the reader is encouraged to contact us at [email protected]. The parameters of the model are detailed in Table 1 of this Appendix and can be found in the PDF file following this document. The Table includes the variable name of the parameter, a description, and the formula used to calculate the value of the parameter in the model (Also included in the Table are information related to the Monte Carlo simulation and sensitivity analysis that will be addressed later.). The formulas reference keywords that are used in TreeAge Pro (Release 8; TreeAge Software Inc., Williamstown, MA; 2004): Discount - The discounting function employed by TreeAge. The three arguments enclosed indicate (in order) the parameter to be discounted, the discount rate (3% in the base model), and the periods to be used for discounting (_stage in this case, see below). _stage - The Markov cycle, in this case, 1 year. A copy of the tree (in TreeAge Pro ® format) is available by request to [email protected]. The purpose of the model was to build a decision tree that mimicked the path of a patient undergoing autologous stem cell transplant (ASCT) for Diffuse Large B-Cell Lymphoma (DLBC). We split the tree into three distinct sections. First, patients went through aphereses sessions to collect a sufficient number of cells. Patients were assigned an age and weight based on the distributions found in the trial. The weight was used to calculate the price of plerixafor and G-CSF. At each node, patients faced a probability of collecting sufficient number of cells for transplant. The goal in the trial was to achieve 5x10 6 CD34+ per kg of blood in four apheresis sessions, though in some cases patients were transplanted with less. If a patient collected a sufficient number of cells they went to transplant. The patient was assigned a tracker variable for the number of cells they achieved, either between 2x10 6 and 5x10 6 cells or greater than 5x10 6 cells. If a patient did not achieve sufficient number of cells, they went through another apheresis session, stopped treatment or entered the rescue procedure. The rescue procedure was designed for patients that failed to achieve 0.8x10 6 cells after two apheresis sessions or 2x10 6 cells after four apheresis sessions. Patients went through up to four apheresis sessions. After the fourth apheresis session, patients either went to transplant even if they had not achieved 2x10 6 cells, went to rescue, or stopped
Transcript
Technical Appendix to Economic evaluation of plerixafor for stem cell mobilization in people with non-Hodgkins Lymphoma
The purpose of this appendix is to provide technical detail regarding the model
used in our paper, as suggested by The Panel on Cost-Effectiveness in Health and Medicine.1 For the reader familiar with these methods, this information should provide sufficient information to replicate our results given the same data. Other readers should find this appendix useful for assessing the validity of our methods, evaluating the source of parameters used in the model, or how specific assumptions or methods were tested. If after reviewing this appendix important questions remain unanswered, the reader is encouraged to contact us at [email protected]. The parameters of the model are detailed in Table 1 of this Appendix and can be found in the PDF file following this document. The Table includes the variable name of the parameter, a description, and the formula used to calculate the value of the parameter in the model (Also included in the Table are information related to the Monte Carlo simulation and sensitivity analysis that will be addressed later.). The formulas reference keywords that are used in TreeAge Pro (Release 8; TreeAge Software Inc., Williamstown, MA; 2004):
Discount - The discounting function employed by TreeAge. The three
arguments enclosed indicate (in order) the parameter to be discounted, the discount rate (3% in the base model), and the periods to be used for discounting (_stage in this case, see below).
_stage - The Markov cycle, in this case, 1 year. A copy of the tree (in TreeAge Pro® format) is available by request to [email protected]. The purpose of the model was to build a decision tree that mimicked the path of a patient undergoing autologous stem cell transplant (ASCT) for Diffuse Large B-Cell Lymphoma (DLBC). We split the tree into three distinct sections. First, patients went through aphereses sessions to collect a sufficient number of cells. Patients were assigned an age and weight based on the distributions found in the trial. The weight was used to calculate the price of plerixafor and G-CSF. At each node, patients faced a probability of collecting sufficient number of cells for transplant. The goal in the trial was to achieve 5x106 CD34+ per kg of blood in four apheresis sessions, though in some cases patients were transplanted with less. If a patient collected a sufficient number of cells they went to transplant. The patient was assigned a tracker variable for the number of cells they achieved, either between 2x106 and 5x106 cells or greater than 5x106 cells. If a patient did not achieve sufficient number of cells, they went through another apheresis session, stopped treatment or entered the rescue procedure. The rescue procedure was designed for patients that failed to achieve 0.8x106 cells after two apheresis sessions or 2x106 cells after four apheresis sessions. Patients went through up to four apheresis sessions. After the fourth apheresis session, patients either went to transplant even if they had not achieved 2x106 cells, went to rescue, or stopped
treatment. All probabilities for collecting sufficient number of cells were taken from the trial. The second part of the model captured what happened while patients were waiting for engraftment. Previous research has indicated that transplanting with a lower number of cells leads to delayed engraftment.2-8 Therefore, patients faced different costs based on the number of cells used in the transplant (based on the tracker variable from the first part of the tree). They also accumulated a number of QALYs based on the time they were in the hospital waiting to engraft. The final part of the model tracked the long-term outcomes of patients after they had engrafted. We chose to examine only patients with DLBC because we could get a more precise estimate of the rates of cancer recurrence post-transplant. Fenske and associates compared the outcomes among patients with DLBC who had received rituximab pre-transplant to those that did not.9 They reported progression-free survival at three years of 50% and an overall survival of 57%. Sohn and associates reported an overall survival at 2 years of 46% after comparing the clinical outcomes of patients with DLBC and peripheral T-cell lymphomas.10 Vose and associates looked at the survival of patients undergoing ASCT after first relapse or second complete remission.11 They found an overall survival of 44%. Mournier and associates looked only at patients achieving a complete remission and found a survival of 76% at five years.12 Presumably, the differing survival estimates were the result of different inclusion criteria. We used the probability of recurrence from Fenske and associates because they examined patients who were given rituximab. Rituximab has been shown to reduce the rate of progression in patients with Non-Hodgkins Lymphoma and is now considered the standard of care. The effects of different rates of recurrence were evaluated using sensitivity analysis.
In our model, patients could have a recurrence of the lymphoma at one, two and three years after transplantation. Fenske and associates reported overall risk cancer progression after 1 and 3 years to be 0.38 and 0.5, respectively. To calculate the risk of death after two years we used a linear interpolation. Out of 100 patients, 62 are expected to be cancer-free after year two and 50 are expected be cancer-free after year three, we assumed that six would die each in years two and three. So, the probability of death at year two is 6/62, or 0.097. The probability of recurrence at year three was 6/56, or 0.107. The first time through the post-transplant part of the tree, patients faced the probability of recurring one year post-transplant. If the cancer recurred, we assumed that they died, since the survival for recurrence after ASCT is very low. If the cancer did not recur, the patient faced a probability of dying based on the age they were assigned in part one of the tree. The probability of death was taken from a life table for the general population. If the patient survived they went through the post-transplant part of the tree a second time, this time one year older. During the second and third time through the post-transplant tree, patients faced a probability of recurrence. Most patients with DLBC lymphoma have a recurrence of the cancer within three years after transplant. Therefore, after three years patients’ risk of death was assumed to be the same as that of the general population. There is no indication that plerixafor has any adverse effects on long-term mortality or morbidity. Estimating the Cost of Medical Treatment
We took the amount of resources utilized from the trial and used costs from Medicare Allowable 2010 where possible. Patients went through four days of G-CSF prior to going through apheresis, regardless of which arm of the study they were assigned to. Also included in this pre-apheresis cost was the cost of hospital admission, daily physician charges and nursing charges for the injection. The cost during each day of apheresis consisted of one dose of G-CSF, the cost of apheresis, physician charges and nursing charge for each injection. Patients in the treatment arm had the additional cost of plerixafor. The price of G-CSF and plerixafor were based on the weight assigned to each patient at the beginning of the model. Weights were sampled from a uniform distribution where the minimum and maximum values were the minimum and maximum weights from the trial. After patients collected sufficient number of cells they faced the cost of transplant and the costs incurred while waiting to engraft. We tracked the number of hospital days, doses of antibiotics, units of red blood cells and units of platelets for each patient. Since previous research suggests that lower cell count leads to delayed engraftment and higher utilization, we calculated an average total cost for each level of cells collected, less than 2x106, 2 to 5x106, and greater than 5x106. We assumed that no additional costs were incurred once patients had fully engrafted and were released from the hospital. Patients received acyclovir, valacyclovir, or both. The cost of acyclovir, 400 mg tablet, was determined by using an average of May 2010 prices obtained from the web sites of Costco, Kmart, Drugstore.com, and Healthwarehouse.com. The prices for each pill were, respectively, $.2376 each, $.083 each, $.4166 each and $.4166 each for an average of $.2885 each. The cost of valacyclovir HCL, 500 mg tablet, was determined by using an average of May 2010 prices obtained from the web sites of Costco, Drugstore.com, and Healthwarehouse.com. The prices for each pill were, respectively, $5.190 each, $5.6663 each, and $5.86 each for an average of $5.572 each. The costs of red blood cells and platelets were taken from Medicare Allowable 2010 (P9021 and P9019, respectively). The prices of plerixafor were obtained from the Medicare allowable charge based on the average sales price. The price of plerixafor used was $268.50 per mg. The price of G-CSF (Filgastrim) is the average of the price for 480 mcg ($330.684) and the price for 300 mcg ($212.548), for an average price of $.06987/microgram. The daily physician charge for hospital visits was determined by finding a weighted average of physician charges for each type of visit. In this case, hospital visits were limited to levels II ($74.47), III ($107.02) and ICU ($279.73). The allowable Medicare charge was determined for each type of visit using www.cms.gov/PFsLookup . The number of occurrences of each type of day was counted for each patient in the study and totaled. The average charge was then determined by multiplying the number of days by the applicable charge, totaling the results and dividing by the number of days. The average physician charge for the G-CSF arm was $99.53 and for the Plerixafor plus G-CSF arm was $92.62. The average physician charge used in the model was the average of these last two numbers, or $96.08. The Utility Loss Associated with Diffuse Large B-Cell Lymphoma
There have been a number of studies that examine the utilities of patients with
Non-Hodgkins Lymphoma, but few have looked specifically at patients undergoing stem cell transplantation. Van Agthoven and associates compared the utilities of patients undergoing peripheral blood stem cell transplantation to those undergoing autologous bone marrow transplant.13 They found the utilities of NHL patients the day before transplantation, 14 days post-transplantation, and three months post-transplantation to be 0.75, 0.53, and 0.78, respectively. We used these estimates because they specifically examined the utility loss associated with patients undergoing transplantation and the baseline utilities were similar to those found in other studies.14, 15 In our model, patients were assigned a utility of 0.75 while undergoing apheresis, 0.53 during engraftment, and 0.78 post-engraftment. During apheresis and engraftment, “_stage” represented one day, so the utilities were divided by 365 to give a “daily QALY.” After engraftment “_stage” represented one year and utilities acquired post-engraftment were discounted at 3%. Since patients were accumulating QALYs without aging in the model prior to engraftment, patients who took longer to get to the post-engraftment part of the tree accumulated more QALYs than those who went through quickly. Since patients in the placebo arm went through more apheresis sessions, they accumulated more QALYs before they entered the post-engraftment part of the tree and began aging. This process represents a conservative analysis because patients in the placebo arm will have accumulated more QALYs even though they took longer to get to transplant. In reality, we would expect patients who spend more time undergoing apheresis and waiting to engraft to accumulate fewer QALYs than someone who went through faster, given the same life-expectancy. Issues Related to Sensitivity Analysis No one from the AMD arm went to rescue in the trial. It is possible that future patients will need to go through a rescue procedure after taking plerixafor, which would reduce the cost-effectiveness of plerixafor. We varied the probability of going to rescue in the plerixafor arm to see what would shift the ICER to $50,000/QALY and $100,000/QALY. To get a more conservative estimate, we increased the probability of an unsuccessful fourth apheresis, so that the patients who went to rescue accumulated the costs of four apheresis sessions. We found that the ICER increased to $50,000/QALY if the probability of rescue in the plerixafor arm was 0.38. This occurred if we assumed that 75% of the people who went through four apheresis sessions went to rescue. The ICER increased to $100,000/QALY if the probability of rescue in the plerixafor arm was 0.87. This occurred if we assumed that 90% of the people who went through four apheresis sessions went to rescue. Everybody in the plerixafor arm went to transplant, compared to 70% in the placebo arm. We examined at what level the probability of transplant in the plerixafor arm would need to be to increase the ICER to $50,000/QALY and $100,000/QALY. Again, we varied the probability of a successful fourth apheresis so that the patients who failed to go to transplant accumulated the costs of four apheresis sessions. A probability of transplant of 0.77 would increase the ICER to $50,000/QALY. This was calculated by setting the probability of transplant after the fourth apheresis to 0.54. A
probability of transplant of 0.76 would increase the ICER to $100,000/QALY. This was achieved by setting the probability of transplant after the fourth apheresis to 0.53. We examined the effects of increasing the probability of recurrence after transplant because a higher rate of recurrence would mean fewer QALYs are accumulated after successful transplant. This could shift the ICER above society’s willingness-to-pay. We increased the recurrence in the first year so that the people who did recur would have accumulated a minimal amount of QALYs. A probability of recurrence of 0.87 in the first year would result in an ICER of $50,000/QALY. A 0.97 probability of recurrence would result in an ICER of $100,000/QALY.
We examined how costly the treatment costs post-transplant would need to be for the incremental cost-effectiveness ratio to reach $50,000/QALY and $100,000/QALY. Since we observed that there was little difference in post-transplant costs between the plerixafor and placebo arms and across cell count, we made a new variable for post-transplant cost that was the same for both arms and the same across cell counts. We found that the cost needed to be $275,000 for the ICER to reach $50,000/QALY and $600,000 to reach $100,000/QALY. We then examined how much more expensive the post-transplant costs in the plerixafor arm would need to be relative to the placebo arm, in order for the ICER to reach $50,000/QALY and $100,000/QALY. The post-transplant costs for patients in the plerixafor arm would need to be $60,000 higher than in the placebo arm for the ICER to reach $50,000/QALY, and $145,000 higher to reach $100,000/QALY. We looked at how sensitive our results were to the price of plerixafor. The current price of plerixafor is $268.512/mg. The proper dose is 240mcg/kg of body weight. The price at which the ICER became $50,000/QALY was $2,400/mg. A price of $5,500/mg resulted in an ICER of $100,000/QALY. There is no price at which plerixafor dominates, presumably because all of the patients in the plerixafor arm went to transplant and thus accumulated all of the relevant costs. Since much of the benefit derived from Plerixafor occurs in the future accumulation of QALYs, the effects of discounting need to be examined. We used 3% in the model, resulting in an ICER of $14,574/QALY. Using a discount rate of 5%, the ICER increased to $18,432/QALY. 1. Gold MR, Siegel JE, Russell LB, Weinstein MC. Cost-Effectiveness in Health and
Medicine, 1 edn Oxford University Press: New York, 1996. 2. BENDER JG, TO LB, WILLIAMS S, SCHWARTZBERG LS. Defining a
Therapeutic Dose of Peripheral Blood Stem Cells. J. Hematother. 1992; 1(4): 329-341.
et al. Peripheral Blood Progenitor Cell Transplantation in 118 Patients with Hematological Malignancies: Analysis of Factors Affecting the Rate of Engraftment. J. Hematother. 1994; 3(3): 185-191.
4. Weaver C, Hazelton B, Birch R, Palmer P, Allen C, Schwartzberg L et al. An
analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy. Blood 1995; 86(10): 3961-3969.
5. Bensinger W, Appelbaum F, Rowley S, Storb R, Sanders J, Lilleby K et al.
Factors that influence collection and engraftment of autologous peripheral-blood stem cells. J. Clin. Oncol. 1995; 13(10): 2547-2555.
6. Glaspy JA, Shpall EJ, LeMaistre CF, Briddell RA, Menchaca DM, Turner SA et
al. Peripheral Blood Progenitor Cell Mobilization Using Stem Cell Factor in Combination With Filgrastim in Breast Cancer Patients. Blood 1997; 90(8): 2939-2951.
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al. Hematopoietic recovery in cancer patients after transplantation of autologous peripheral blood CD34+ cells or unmanipulated peripheral blood stem and progenitor cells. Transfusion (Paris). 1998; 38(2): 199-208.
8. Ketterer N, Salles G, Raba M, Espinouse D, Sonet A, Tremisi P et al. High
9. Fenske TS, Hari PN, Carreras J, Zhang M-J, Kamble RT, Bolwell BJ et al. Impact
of Pre-transplant Rituximab on Survival after Autologous Hematopoietic Stem Cell Transplantation for Diffuse Large B Cell Lymphoma. Biol. Blood Marrow Transplant. 2009; 15(11): 1455-1464.
10. Sohn BS, Park I, Kim EK, Yoon DH, Lee SS, Kang BW et al. Comparison of
clinical outcome after autologous stem cell transplantation between patients with peripheral T-cell lymphomas and diffuse large B-cell lymphoma. Bone Marrow Transplant. 2009; 44(5): 287-293.
11. Vose JM, Rizzo DJ, Tao-Wu J, Armitage JO, Bashey A, Burns LJ et al.
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12. Mounier N, Gisselbrecht C, Briere J, Haioun C, Feugier P, Offner F et al.
Prognostic Factors in Patients With Aggressive Non-Hodgkin's Lymphoma Treated by Front-Line Autotransplantation After Complete Remission: A Cohort Study by the Groupe d'Etude des Lymphomes de l'Adulte. In: J. Clin. Oncol., 2004. pp 2826-2834.
13. van Agthoven M, Vellenga E, Fibbe WE, Kingma T, Uyl-de Groot CA. Cost analysis and quality of life assessment comparing patients undergoing autologous peripheral blood stem cell transplantation or autologous bone marrow transplantation for refractory or relapsed non-Hodgkin's lymphoma or Hodgkin's disease: a prospective randomised trial. Eur. J. Cancer 2001; 37(14): 1781-1789.
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Name Description Formula Dist
Type
Value in
model
Low
Value
High
Value
Sensitivity
Analysis
Sensitivity
Analysis
Starting Age Starting age in years Starting age Normal mean=56.5
SD=11.6
AMD Cost Cost of Plerixafor (AMD3100) Weight*240*
AMD_Pricevar+21.56
n/a
AMD_Pricevar Price of Plerixafor per kg of
body weight
n/a n/a 0.26851 0 8000
cost_2to5_cells_AMD Costs post-transplant for
patients in AMD arm
transplanted with 2 to 5x10^6
CD34+ cells
n/a n/a 28205.2 680000
cost_2to5_cells_placebo Costs post-transplant for
patients in placebo arm
transplanted with 2 to 5x10^6
CD34+ cells
n/a n/a 25790.79 680000
cost_greater5cells_AMD Costs post-transplant for
patients in AMD arm
transplanted with greater
than 5x10^6 CD34+ cells
n/a n/a 26753.39 680000
cost_greater5cells_placebo Costs post-transplant for
patients in placebo arm
transplanted with greater
than 5x10^6 CD34+ cells
n/a n/a 27245.64 680000
cost_less2cells_AMD Costs post-transplant for
patients in AMD arm
transplanted with less than
2x10^6 CD34+ cells
n/a n/a 25840.9 680000
cost_less2cells_placebo Costs post-transplant for
patients in placebo arm
transplanted with less than
2x10^6 CD34+ cells
n/a n/a 26511.74 680000
cost_admission Cost of hospital admission n/a n/a 206.74
cost-discharge Cost of hospital discharge n/a n/a 73.13
cost_nurse_injection Nursing charge for injection n/a n/a 22.74
