Cost-Effectiveness Of Midostaurin In The Treatment Of Acute Myeloid Leukemia With The FLT3 Mutation In Spain

Figures & data

Table 1 Regimens Considered In Each Treatment Phase

Treatments	Active Principle	Regimen
1st line chemotherapy: intervention therapy
Induction (cytarabine + daunorubicin + midostaurin)	Cytarabine	200mg/m^2/day (days 1–7)
	Daunorubicin	60mg/m^2/day (days 1–3)
	Midostaurin	50 mg twice a day (days 8–21)
Consolidation (high dose cytarabine + midostaurin)	High dose cytarabine	3,000mg/m^2/day twice a day (days 1, 3, 5)
	Midostaurin	50mg twice a day (days 8–21)
Maintenance (midostaurin)	Midostaurin	50mg twice a day (days 1–28)
1st line chemotherapy: Comparator treatment
7 + 3 (cytarabine + daunorubicin)	Cytarabine	200mg/m^2/day (days 1–7)
	Daunorubicin	60mg/m^2/day (days 1–3)
High dose cytarabine	High dose cytarabine	3,000mg/m^2/day twice a day (days 1,3,5)
2nd line chemotherapy
FLAG-IDA (fludarabine + cytarabine + idarubicin)	Fludarabine	30 mg/m^2 (days 1–5)
	Cytarabine	2,000 mg/m^2/day (days 1–7)
	Idarubicin	10 mg/m^2/day (days 1–3)
MEC (mitoxantrone + etoposide + cytarabine)	Mitoxantrone	8 mg/m^2/day, (days 1–6)
	Etoposide	80 mg/m^2/day, (days 1–6)
	Cytarabine	1,000 mg/m^2/day, (days 1–6)
Other treatments^a
7 + 3 (cytarabine + idarubicin)	Cytarabine	200mg/m^2/day (days 1–7)
	Idarubicin	12 mg/m^2/day, (days 1–3)

Notes: ^aIncluded in the sensitivity analysis. In the opinion of experts, regimens based on cytarabine and idarubicin are common in Spain as induction therapy, so a sensitivity analysis was also carried out in which the costs of induction treatment with idarubicin and daunorubicin were included.

Figure 1 Model structure.

Table 2 Utilities Associated With The Treatment Phases

State	Value	Source
Induction^a	0.648	Uyl-DE Groot et al, 1998^Citation13
Consolidation^a	0.710	Batty et al, 2014^Citation14
Maintenance^a	0.810	Batty et al, 2014^Citation14
CR post 1st line (no relapse)	0.830	Leunis et al, 2014^Citation15
Relapse	0.780	NICE, 2018^Citation9
HSCT^a,b	0.613	Crott (2010) & Grulke (2012)^Citation16,Citation17
HSCT recovery^b	0.810	Crott (2010) & Grulke (2012)^Citation16,Citation17
HSCT follow up (after 1st line) ^b	0.826	Crott (2010) & Grulke (2012)^Citation16,Citation17

Notes: ^aIncludes the disutility associated with treatment. ^bUtility values used in the model for SCT treatment, recovery, and post-SCT recovery, were mapped from published (EORTC) Quality of Life Core Questionnaire QLQ-C30 data (Grulke et al 2012) using an algorithm developed by Crott et al (2010) which calculated EQ-5D utility based on QLQ-C30 scores. The QLQ-C30 data published by Grulke et al presented scores specific to different stages of stem cell therapy (before SCT, during hospitalization, up to 6 months after SCT, and >1 year after SCT). The algorithm developed by Crott, et al was then applied to this data in order to obtain EQ-5D utility scores: EQ-5D utility = 0.85927770–0.0069693*(Physical Functioning) – 0.0087346*(Emotional Functioning) – 0.0039935*(Social Functioning) + 0.0000355*(Physical Functioning)² + 0.0000552*(Emotional Functioning)² + 0.0000290*(Social Functioning)² + 0.0011453*(Constipation) +0.0039889*(Diarrhoea) + 0.0035614*(Pain) – 0.0003678*(Sleep) – 0.0000540*(Diarrhoea)²+0.0000117*(Sleep)².

Table 3 Drug Prices Before And After The Discount According To RDL 8/2010¹⁷

Drug	PVL	Discount. RDL	PVL- Discount. RDL
Midostaurin (Rydapt^®) (25 mg, 56 capsules)	€ 6673.77	4%	€ 6406.82
Cytarabine gpe (500 mg, 1 vial)	€ 7.19	-	€ 7.19
Cytarabine gpe (1 g, 1 vial)	€ 14.38	-	€ 14.38
Cytarabine gpe (2 g, 1 vial)	€ 28.76	-	€ 28.76
Daunoblastin (daunorubicin) (20 mg, 1 vial)	€ 4.20	15%	€ 3.57
Fludarabine gpe (25 mg/mL, 2 mL)	€ 49.77	-	€ 49.77
Mitoxantrone gpe (10 mg, 1 vial)	€ 23.46	-	€ 23.46
Etoposide gpe (20 mg/mL, 1 vial, 2 mL)	€ 10.06	-	€ 10.06
Idarubicin gpe (10 mg, 1 vial)^a	€ 81.80	-	€ 81.80

Notes: ^aIncluded in the sensitivity analysis. In the opinion of experts, the schemes based on the use of cytarabine and idarubicin are also common in Spain induction, so a sensitivity analysis was also carried out in which the costs of the induction treatment with idarubicin and daunorubicin were considered.

Abbreviations: GPE, Generic Pharmaceutical Equivalent; PVL, ex-factory price; RDL, Royal Decree Law.

Table 4 Cost Per Treatment Cycle

Treatments	Cost/Cycle
1^st line chemotherapy: intervention therapy
Induction (cytarabine + daunorubicin + midostaurin)	€ 6,521.41
Consolidation (high dose cytarabine + midostaurin)	€ 6,859.79
Maintenance (midostaurin)	€ 12,813.65
1^st line chemotherapy: Comparator treatment
7 + 3 (cytarabine + daunorubicin)	€ 114.59
High dose cytarabine	€ 452.97
2^nd line chemotherapy
FLAG-IDA (fludarabine + cytarabine + idarubicin)	€ 1,340.81
MEC (mitoxantrone + etoposide + cytarabine)	€ 514.44
Other treatments^a
7 + 3 (cytarabine + idarubicin)	€ 786.53

Notes: ^aIn the opinion of experts, regimens based on cytarabine and idarubicin are also common in induction therapy in Spain, so a sensitivity analysis was carried out that included the costs of induction therapy with idarubicin and daunorubicin.

Table 5 Unit Costs Of The Health Resources Used In The Analysis

Resource	Unit Cost
Hospitalizations
Hospitalization for chemotherapy (cost/stay)^a	€ 23,362.91
Hospitalization for allogeneic HSCT (cost/process)^b	€ 46,204.70
Additional hospitalization in a patient with no complete remission (cost/day)^c	€ 1,146.99
Additional hospitalization in a patient in remission (cost/day)^d	€ 1,383.03
Mortality cost (cost/process)^e	€ 7,635.51
Other health resources
FLT-3 test	€ 327.96
Day hospital visit	€ 84.32
Emergency visit	€ 177.82
Specialist visit	€ 84.32
Bone marrow aspiration	€ 63.92
Complete blood count and biochemistry	€ 94.86

Notes: ^aDRG 205.00: Acute myeloid leukemia with no mention of remission being achieved. ^bAllogeneic bone marrow transplant (cost/hospitalization). ^cEstimated from the cost of the stay equivalent to DRG 205.02 “Acute Myeloid Leukemia in Recurrence” and the length of stay for this DRG stipulated in the CMBD. ^dEstimated from the cost of the stay equivalent to DRG 205.01 “Acute Myeloid Leukemia in Remission” and the length of stay for this DRG stipulated in the CMBD. ^eAverage cost of hospitalization for a patient with a fatal termination (CMBD).

Table 6 Resource Use In The Complete Remission And No Complete Remission States

		Complete Remission				No Complete Remission
			0-6 Months	6-12 Months	2-5 Years	6+ Years
Specialist visits	% patients	100%	100%	100%	100%	100%
	Frequency/cycle	2.0	0.4	0.2	0.1	3
Emergency room visits	% patients	60%	15%	7.5%	0%	62.5%
	Frequency/cycle	0.25	0.25	0.03	0.0	1.5
Bone marrow aspiration	% patients	100%	50%	20%	0%	100%
	Frequency/cycle	0.2	0.2	0.03	0.0	1
Complete blood count and biochemistry	% patients	100%	100%	100%	0%	100%
	Frequency/cycle	2.0	0.4	0.2	0.0	3
Hospitalizations	% patients	2.5%	2.5%	2.5%	0%	100%
	Frequency/cycle	1.0	2.5	0.2	0.0	1
	Duration (days)	12.5	12.5	10	0.0	25–30

Table 7 Univariate Deterministic Sensitivity Analysis

Parameter	Base Scenario	Sensitivity Analysis Scenario
Discount on benefits and costs (0–5%)^a,b	3%	0% 5%
Modification of the cost of HSCT (DRG 803: € 61,000.07)^c	€ 46,204.70	€ 61,001.07
Modification of the cost of HSCT (highest cost available: € 110,276.59)^d	€ 46,204.70	€ 110,276.59
Utility in the state of complete no remission (0.655)^b	0.780	0.655
Different cure point (6.2 years)^b,e	3 years	6.2 years, derived from the maximum follow-up of patients in RATIFY
Different mortality adjustment after the fourth year (=/x2 mortality, general population)^b	15% higher than the general population	Same as the general population. Twice as high as the general population
PVL reduction for midostaurin (20-30-40%)	100%	60% 70% 80%
Modification of 2nd line therapy costs (± 20%)	100%	80% 120%
Modification of mortality costs (± 20%)	100%	80% 120%
Replacement of daunorubicin with idarubicin^f	Daunorubicin 60mg/m2/day (days 1–3)	Idarubicin 12 mg/m^Citation2/day (days 1–3)
Modification of non-pharm health costs during 1st line treatment (± 20%)	100%	80% 120%

Notes: ^aBased on economic evaluation guidelines. ^bBased on NICE recommendations. ^cCost of HSCT equivalent to the cost of DRG 803 (“Allogenic bone marrow transplant”). ^dThe highest cost of allogeneic HSCT found in the available evidence (eSalud).¹⁸ eIn keeping with the follow-up time in the RATIFY study. ^fBased on expert opinion.

Abbreviation: PVL, ex-factory price.

Table 8 Results Of The Cost-Effectiveness And Cost-Utility Analyses. Base Case

	Midostaurin + Chemotherapy	Chemotherapy	Incremental
Cost
Pharmacological cost	€ 61,250	€ 1,798	€ 59,452
Induction	€ 7,973	€ 466	€ 7,507
Consolidation	€ 12,881	€ 744	€ 12,138
Maintenance	€ 39,870	€ 0	€ 39,870
2nd line therapy	€ 527	€ 589	€ −62
Cost of healthcare resources (non-pharmacological)	€ 106,798	€ 121,374	€ −14,576
During treatment	€ 66,568	€ 60,439	€ 6,129
After treatment	€ 40,230	€ 60,935	€ −20,705
HSCT costs	€ 34,723	€ 31,315	€ 3,409
Costs of mortality	€ 5,082	€ 5,413	€ −331
TOTAL COST	€ 207,854	€ 159,900	€ 47,955
Effectiveness
LYG	11.73	10.27	1.46
QALYs	9.45	8.22	1.23
ICER (€ per LYG):	€ 32,854
ICUR (€ per QALY gained):	€ 38,985

Note: The values that are not in bold are components of the items in bold. 

Abbreviations: QALY, Quality Adjusted Life Year; LYG, Life year gained; ICER, Incremental Cost Effectiveness Ratio; ICUR, Incremental Cost Utility Ratio.

Figure 2 Univariate sensitivity analysis. a. Based on economic evaluation guidelines. b. Based on NICE recommendations. c. In keeping with the follow-up time in the RATIFY study. d. The highest cost of allogeneic HSCT found in the available evidence (eSalud). e. Cost of HSCT equivalent to the cost of DRG 803 (“Allogenic bone marrow transplantation”). f. Based on expert opinion.

Abbreviations: AE, adverse events; PVL, ex-factory price.

Figure 3 Probabilistic sensitivity analysis.

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