Cost-effectiveness analysis of second-line tyrosine kinase inhibitor treatment for chronic myelogenous leukemia

Figures & data

Table 1. TKI sequences evaluated for patient populations.

Resistant to 1st line imatinib		Intolerant to 1st line imatinib
2nd line	3rd line	2nd line	3rd line
High-dose imatinib	Dasatinib	NA	NA
High-dose imatinib	Nilotinib	NA	NA
Dasatinib	Bosutinib	Dasatinib	Bosutinib
Dasatinib	Nilotinib	Dasatinib	Nilotinib
Nilotinib	Bosutinib	Nilotinib	Bosutinib
Nilotinib	Dasatinib	Nilotinib	Dasatinib

Figure 1. Model schematic.

Figure 2. Detailed schematic of ‘second-line TKI (first 12 months)’ health states (dashed grey box).

Figure 3. Efficacy inputs—response, transformation, and death.

Table 2. Model inputs.

Parameter	Base case value	Source
Relative risk for imatinib-resistant vs overall population
MMR and CCyR	DAS, NIL: 0.93 HDI: 0.41*	Based on 24-month response rates presented in Shah et al.20, Kantarjian et al.24, and Kantarjianet al.26
MCyR	DAS, NIL: 0.93 HDI: 0.62*	Based on 24-month response rates presented in Shah et al.20, Kantarjian et al.24, and Kantarjian et al.26
Transformation – first 12 months	DAS, NIL: 1.06 HDI: N/A	Based on progression-free survival at 6 years presented in Shah et al.21; nilotinib’s RR is assumed to be the same as dasatinib’s, due to data limitations
Death – first 12 months	DAS, NIL: 1.07 HDI: N/A	Based on overall survival at 6 years presented in Shah et al.21; nilotinib’s RR is assumed to be the same as dasatinib’s due to data limitations
Relative risk for imatinib-intolerant vs overall population
MMR, CCyR, and MCyR	DAS, NIL: 1.20	Based on 24-month response rates presented in Shah et al.20 and Kantarjian et al.24
Transformation – first 12 months	DAS, NIL: 0.82	Based on progression-free survival at 6 years presented in Shah et al.21; nilotinib’s RR is assumed to be the same as dasatinib’s due to data limitations
Death – first 12 months	DAS, NIL: 0.76 HDI: N/A	Based on overall survival at 6 years presented in Shah et al.21; nilotinib’s RR is assumed to be the same as dasatinib’s due to data limitations
Loss of response
3-month probability of loss of response	2nd line: DAS, HDI: 0.79% NIL: 0.82% 3rd line: DAS, NIL: 3.05% BOS: 4.74%	Based on Shah et al.21, Giles et al.23; Garg et al.922, and Khoury et al.25; 2nd line high-dose imatinib is assumed to be the same as dasatinib due to data limitations
3-month probability of discontinuing due to toxicities	HDI: 6.3% DAS: 0.8% NIL: 1.1% BOS: 2.7%	Based on Kantarjian et al.26, Shah et al.20, Kantarjian et al.26, and Khoury et al.25
Post-TKI therapy
3-month probability of transformation	4.2%	Based on transformation risks for patients without cytogenetic response in Hochhaus et al.13, assuming constant risk over time.
3-month probability of death	3.6%	Based on survival curves for patients failing imatinib in chronic phase CML27, assuming constant risk over time
Advanced phases
3-month probability of death	3.6%	Based on survival curves for patients failing imatinib in advanced and blast phase CML27, assuming constant risk over time
Costs
Drug acquisition cost (per month)	HDI: $14,805.72 DAS: $8326.72 NIL: $8445.59 BOS: $7541.63	Based on dosing, acquisition cost, and application of dose intensity (see text)
Monitoring cost (at initiation)	HDI: $687.04 DAS: $0.00 NIL: $360.36 BOS: $515.28	Monitoring tests associated with every TKI treatment based on FDA labels1–4; unit costs were obtained from Medicare 2014 payment limits24
Monitoring cost (per month)	HDI: $182.90 DAS: $180.18 NIL: $235.35 BOS: $182.90
Adverse event management (per month)	HDI: $414.27 DAS: $55.29 NIL: $75.01 BOS: $142.33	Incidence rates were based on published clinical trials25^,26^,28^,29; hospitalization frequency and outpatient management were based on NICE HTA assessment30 and assumptions; hospitalization costs were obtained from AHRQ’s Healthcare Utilization Project and outpatient management; unit costs based on Medicare 2014 payment limits
Routine clinic visits (per month)	On TKI: $53.13 Off TKI: $115.92	Resource use based on NICE HTA assessment30; unit costs of resources based on Medicare payment limits24
Bone marrow cytogenetic test	$1597.43	Payment, lab fee, and physician fees for bone marrow biopsy, aspiration, and cytogenetic tests Medicare payment limits31
Quantitative PCR	$316.22	One BCR/ABL1 test and one clinic visit Medicare payment limits31
Cost of care in advanced phases (per month)	$2303	Resource use based on NICE HTA assessment30; unit costs of resources based on Medicare payment limits24
Utilities
Utility weights	Responders: 0.92 Non-responders and post-TKI: 0.83 Advanced phases: 0.66	Based on Szabo et al.32
Utility decrement for toxicity-related discontinuation:	−0.06 QALYs	Based on a temporary utility of 0.5930 for an assumed 3 months

RR, relative risk vs the overall trial population; DAS: dasatinib; NIL: nilotinib; HDI: high-dose imatinib.

*Due to lack of time to response curves for high-dose imatinib, relative risks are applied to dasatinib response curves.

Table 3. Model results for the imatinib-resistant population.

	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6
	Imatinib – 800 mg Nilotinib – 800 mg	Imatinib – 800 mg Dasatinib – 100 mg	Dasatinib – 100 mg Bosutinib – 500 mg	Dasatinib – 100 mg Nilotinib – 800 mg	Nilotinib - 800 mg Bosutinib – 500 mg	Nilotinib – 800 mg Dasatinib – 100 mg
Lifetime
Time spent on TKIs	1.6 years	1.6 years	4.4 years	4.4 years	3.9 years	3.9 years
Survival	6.4 years	6.4 years	8.1 years	8.4 years	7.9 years	8.2 years
QALYs	4.9 years	4.9 years	6.7 years	6.8 years	6.4 years	6.6 years
Total cost	$334,281	$333,487	$515,602	$529,67	$474,515	$489,143
Second-line therapy
Percentage of patients initiating	100%	100%	100%	100%	100%	100%
Time on treatment	10.7 months	10.7 months	44.6 months	44.6 months	37.7 months	37.7 months
Total cost	$169,429	$169,429	$391,507	$391,507	$339,430	$339,430
Third-line therapy
Percentage of patients initiating	92%	92%	85%	85%	91%	91%
Time on treatment	8.9 months	9.1 months	7.9 months	7.7 months	8.6 months	8.5 months
Total cost	$82,294	$81,418	$65,459	$70,725	$71,130	$76,016
Chronic phase, without TKI treatment
Percentage of patients	69%	69%	64%	63%	69%	68%
Time in phase	23.2 months	23.1 months	20.1 months	19.9 months	21.8 months	21.5 months
Total cost	$2685	$2673	$2325	$2307	$2526	$2495
Accelerated and blast phase
Percentage of patients	57%	57%	44%	50%	47%	54%
Time in phase	34.5 months	34.6 months	24.3 months	28.2 months	26.6 months	30.8 months
Total cost	$79,872	$79,966	$56,310	$65,227	$61,429	$71,201

Table 4. Model results for the imatinib-intolerant population.

	Sequence 3	Sequence 4	Sequence 5	Sequence 6
	Dasatinib – 100 mg Bosutinib – 500 mg	Dasatinib – 100 mg Nilotinib – 800 mg	Nilotinib – 800 mg Bosutinib – 500 mg	Nilotinib – 800 mg Dasatinib – 100 mg
Lifetime
Time spent on TKIs	5.4 years	5.3 years	4.6 years	4.6 years
Survival	8.9 years	9.2 years	8.5 years	8.8 years
QALYs	7.4 years	7.6 years	7.0 years	7.2 years
Total cost	$616,170	$629,765	$551,783	$565,802
Second-line therapy
Percentage of patients initiating	100%	100%	100%	100%
Time on treatment	56.8 months	56.8 months	47.1 months	47.1 months
Total cost	$497,723	$497,723	$422,882	$422,882
Third-line therapy
Percentage of patients initiating	84%	84%	89%	89%
Time on treatment	7.5 months	7.4 months	8.2 months	8.1 months
Total cost	$62,694	$67,765	$68,055	$72,752
Chronic phase, without TKI treatment
Percentage of patients	63%	62%	67%	66%
Time in phase	19.2 months	19.1 months	20.9 months	20.6 months
Total cost	$2227	$2210	$2417	$2388
Accelerated and blast phase
Percentage of patients	43%	49%	46%	52%
Time in phase	23.1 months	26.8 months	25.3 months	29.3 months
Total cost	$53,526	$62,066	$58,428	$67,779

Table 5. Results of scenario analyses.

Scenario	Imatinib-intolerant Sequence 4 (DAS → NIL)		Imatinib-resistant Sequence 4 (DAS → NIL)
	QALYs	Cost ($)	QALYs	Cost ($)
Base case	7.6	$630,376	6.8	$530,251
Scenario 1a	5.0	$247,762	4.9	$235,445
Scenario 1b	7.6	$625,600	6.8	$526,379
Scenario 2	7.7	$637,282	6.9	$533,412
Scenario 3	7.6	$633,452	6.9	$533,463
Scenario 4	7.8	$644,527	7.1	$552,592
Scenario 5	7.4	$614,995	–	–
Scenario 6	7.1	$550,935	5.9	$382,962

DAS, dasatinib; NIL, nilotinib.

Figure 4. (a) One-way sensitivity analysis for imatinib-intolerant population. (b) One-way sensitivity analysis for imatinib-resistant population. *The inputs were varied ± 20% from the base case values.

Table A5. Second-line: observed and interpolated death probabilities.

Dasatinib				Nilotinib
Time	Observed OS	Cumulative probability of death	Incident probability of death	Observed	Cumulative probability 1 − ((1 − Obs PFS)*3.9%)	Incident probability
3 months	99.15%	0.85%	0.86%	97.60%	0.09%	0.09%
6 months	97.89%	2.11%	1.28%	94.10%	0.23%	0.14%
9 months	96.97%	3.03%	0.95%	91.68%	0.33%	0.10%
12 months	95.97%	4.03%	1.04%	87.04%	0.51%	0.18%

Table A6. Third-line: observed and interpolated response rates on bosutinib.

Months	Bosutinib
	Observed			Interpolated
	MMR	CCyR	MCyR	MMR	CCyR	MCyR
2.9			12%	2%	10%	14%
3				2%	10%	14%
5.5			25%	5%	16%	21%
6				6%	17%	22%
9				10%	22%	29%
12	15%	24%	32%	15%	26%	35%
15				21%	30%	40%
18				26%	33%	44%

Table A7. Third-line: observed and interpolated response rates on dasatinib/nilotinib.

Months	Dasatinib or Nilotinib
	Observed			Interpolated
	MMR	CCyR	MCyR	MMR	CCyR	MCyR
3				2%	9%	12%
6				7%	15%	20%
9				12%	19%	26%
12				18%	23%	30%
13	20%	24%	32%	20%	24%	32%
15				24%	26%	35%
18				31%	29%	39%

Table A8. Third-line observed and interpolated probabilities of transformation on dasatinib/nilotinib and bosutinib.

Time	Cumulative probability of an event (1-EFS)	Probability of an event	Probability of transformation (pevent*47.37%)
Dasatinib and Nilotinib
3 months	11.82%	11.82%	5.60%
6 months	25.00%	14.95%	7.08%
9 months	34.12%	12.16%	5.76%
12 months	34.12%	0%	0.00%
	Cumulative probability of progression or death (1-PFS)	Probability of progression or death	Probability of transformation (pPFS event*40.81%)
Bosutinib
3 months	8.22%	8.22%	3.35%
6 months	11.47%	3.54%	1.45%
9 months	17.95%	7.32%	2.99%
12 months	23.52%	6.78%	2.77%

Table A9. Third-line: observed and interpolated probabilities of death on dasatinib/nilotinib and bosutinib.

Time	Observed cumulative probability of death (1-OS)	Probability of death
Dasatinib and Nilotinib
3 months	4.21%	4.21%
6 months	4.21%	0.00%
9 months	4.21%	0.00%
12 months	4.21%	0.00%
Bosutinib
3 months	8.22%	8.22%
6 months	11.47%	3.54%
9 months	17.95%	7.32%
12 months	23.52%	6.78%

Table A1. Second-line: observed and interpolated CCyR rates.

Months	Dasatinib		Nilotinib
	Observed	Interpolated	Observed	Interpolated
3	25%	29%		25%
3.3			22%	26%
6	40%	35%		31%
9	41%	39%		35%
12	45%	43%	31%	38%
15	45%	45%		40%
18	48%	47%		42%
24	50%	51%	44%	45%

Table A2. Second-line: observed and interpolated MCyR rates.

Months	Dasatinib		Nilotinib
	Observed	Interpolated	Observed	Interpolated
2.3			30%^a	29%
2.8	32%	35%	24%^b	31%
3		36%		32%
6		44%		39%
9		50%		44%
12		54%	48%^b	47%
15		57%		50%
18		60%		53%
24	63%	64%	59%^a	57%

^aKantarjian et al.26; ^bKantarjian et al.24.

Table A3. Second-line: observed and interpolated MCyR rates.

Months	Dasatinib		Nilotinib
	Observed	Interpolated	Observed	Interpolated
3		10%		13%
6		16%		20%
9		20%		26%
12		24%	32%	31%
15		28%		36%
18		31%	39%	40%
24	37%	37%		47%

Table A4. Second-line: observed and interpolated transformation probabilities.

Dasatinib			Nilotinib
Transformation			Progression-free survival	Transformation
Time	Observed	Interpolated	Observed	Cumulative probability 1 − ((1 − Obs PFS)*10.8%)	Transition probability
3 months		0.26%	97.60%	0.26%	0.26%
6 months		0.52%	94.10%	0.64%	0.38%
9 months		0.78%	91.68%	0.90%	0.26%
12 months		1.04%	87.04%	1.40%	0.51%
74 months	6.06%	6.06%	NA	NA	NA

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