Bendamustine-rituximab: a cost-utility analysis in first-line treatment of indolent non-Hodgkin’s lymphoma in England and Wales

Figures & data

Figure 1. Treatment pathways. (A) B-R and CHOP-R. B-R: 28-day cycles; bendamustine 90 mg/m²/day on Days 1 and 2; rituximab 375 mg/m² on Day 1; maximum six cycles. CHOP-R: 21-day cycles; cyclophosphamide 750 mg/m² on Day 1; doxorubicin 50 mg/m² on Day 1; vincristine 1.4 mg/m² on Day 1; prednisone 100 mg/m² on Days 1–5; rituximab 375 mg/m² on Day 1; maximum six cycles. (B) CVP-R. CVP-R: 21-day cycles; cyclophosphamide 750 mg/m² on Day 1; vincristine 1.4 mg/m² on Day 1; prednisone 40 mg/m² on Days 1–5; rituximab 375 mg/m² on Day 1; maximum eight cycles. R-maintenance: 375 mg/m² once every 8 weeks (first-line) and once every 3 months (second-line). Second-line treatment doses were taken from the approach by ScHARR14. Early relapse, < 6 months after end of 24 months’ R-maintenance; late relapse, ≥6 months after end of 24 months’ R-maintenance. ASCT, autologous stem cell transplant; B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; CVP, cyclophosphamide, vincristine, and prednisone; FC, fludarabine and cyclophosphamide; HDT, high-dose therapy; R, rituximab.

Table 1. Key clinical and quality-of-life inputs.

Patient characteristics
	Male	Female	Source
Mean age (years)	64.61	62.12	Mean age and gender taken from population
Gender (number of patients)	879	990	statistics for FL patients in England and Wales.
Mean BSA (m^2)	1.971	1.745	Mean BSA taken from Salles et al.18.
First-line response rates
Treatment	Response rate [number (%) of patients]
	CR	PR	Source
B-R (n = 224)	95 (42.41)	108 (48.21)	B-R and CHOP-R response rates taken from the
CHOP-R (n = 223)	62 (27.80)	121 (54.26)	Rummel et al. study. CVP-R response rates
CVP-R	n/a (23.32)	n/a (45.52)	calculated by applying a relative risk of 0.84 to the CR and PR rates for CHOP-R patients.
PFS1 time to event parameters for B-R and CHOP-R
	Value	Distribution	Source
CR intercept	4.1281	Multivariate normal	Time to event parameters based on individual patient data from the Rummel et al. study. Log-normal distribution for complete and non-responders, Weibull distribution for partial responders. The HR for CVP-R was an assumption. The HR for R-maintenance was taken from Salles et al.18.
CR shape	1.6546	Multivariate normal
CR treatment effect of B-R	0.4399	Multivariate normal
PR intercept	3.9020	Multivariate normal
PR shape	1.2458	Multivariate normal
PR treatment effect of B-R	0.5754	Multivariate normal
Non-responder intercept	2.0777	Multivariate normal
Non-responder shape	1.1262	Multivariate normal
Non-responder treatment effect of B-R	−0.7067	Multivariate normal
CVP-R HR (vs CHOP-R)	1.00	SE = 0.00
R-maintenance HR	0.55	SE = 0.0612, log-normal
Utility values
	Value (SE)
State	Base-case	Sensitivity analysis	Source
CR, first line	0.805 (0.018)	0.79 (0.03)	Wild et al.28, with the exception of the value for adverse events, which was taken from the ScHARR model14, and the value for PD used in the sensitivity analysis, which was an assumption.
PR, first line	0.805 (0.018)	0.77 (0.03)
No response, first line	0.805 (0.018)	0.62 (0.06)
Response, second line	0.805 (0.018)	0.77 (0.03)
No response, second line	0.805 (0.018)	0.62 (0.06)
Progressive disease	0.7363 (0.036815)	0.40 (0.02)
Adverse event	0.018 (0.00)	0.018 (0.00)

B, bendamustine; BSA, body surface area; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CR, complete response; CVP, cyclophosphamide, vincristine, and prednisone; FL, follicular lymphoma, HR, hazard ratio; n/a, not applicable; PD, progressive disease; PR, partial response; R, rituximab; SE, standard error.

Table 2. Costs.

Treatment costs
Total acquisition costs
Treatment			Total cost per cycle (£)		Source
CHOP			272.54		British National Formulary29, NHS reference costs 2010–201130 and ScHARR model14
CHOP-R			2,018.84
CVP-R			1,811.73
FC			332.61
FC-R			2,078.91
B-R			2,718.60
HDT			358.10
HDT-R			2,104.40
GCSF			59.00
Stem cell harvest, no ASCT			2,202.00
ASCT			31,424.72
Unit drug administration costs
Treatment			Cost (£)		Source
Chemotherapy alone			265.00		NHS reference costs 2010–201130 and ScHARR model14
R-chemotherapy			334.00
Maintenance therapy			294.00
GCSF administration			147.53
Pharmacy			15.97
Transport			40.32
Monitoring costs—unit costs and frequency by health state
Resource			Unit cost (£)		Source
Hospital visit with haematologist			147.53		NHS reference costs 2010–11^30 and ScHARR model14
CT scan			159.55
Full blood count			6.30
Patient history/physical exam			9.53
Full profile (urea and electrolytes, liver function test, calcium)			17.16
Serum IgG, IgA, IgM, electrophoresis			25.19
Lactate dehydrogenase test			12.74
Third-line therapy costs
Treatment received at second line			Cost at third line (£)		Source
CHOP + observation			12,265		Third-line therapy costs for patients receiving CHOP-containing therapies taken from ScHARR model14.
CHOP + R-maintenance			10,085
CHOP-R + observation			8,644
CHOP-R + R-maintenance			5,857
FC + observation			12,265
FC + R-maintenance			10,085
FC-R + observation			8,644
FC-R + R-maintenance			5,857
HDT(R) + ASCT success			8,644
Grade 3–4 haematological adverse event costs
		Probability			Source
Adverse event	Cost (£)	B-R	CHOP-R	CVP-R
Leukopenia	475.00	0.38202	0.73413	0.11730	Adverse event costs taken from NHS reference costs 2010–201130 and ScHARR model14. Adverse event probabilities taken from the studies by Rummel et al. (B-R and CHOP-R) and Federico et al.32 (CVP-R).
Granulocytopenia	1,555.71	0.24345	0.62698	0.00000
Neutropenia	3,362.14	0.00749	0.03175	0.27700
Febrile neutropenia	5,373.00	0.00000	0.02778	0.00000
Thrombocytopenia	809.00	0.06742	0.05952	0.00000
Anaemia	497.00	0.02622	0.05159	0.06000

ASCT, autologous stem cell transplant; B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CT, computerized tomography; CVP, cyclophosphamide, vincristine, and prednisone; FC, fludarabine and cyclophosphamide; GCSF, granulocyte colony-stimulating factor; HDT, high dose therapy; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; NHS, National Health Service; R, rituximab; R-maintenance, rituximab maintenance.

Table 3. Key results.

Model time-in-state (undiscounted)
Health state	B-R	CHOP-R	CVP-R
PFS1	8.50	6.02	5.23
PFS2	2.46	2.90	3.80
PD	2.10	2.66	2.73
Total	13.07	11.58	11.76
Costs by health state
Health state		B-R costs	CHOP-R costs		Increment	CVP-R costs	Increment
PFS1*		£45,121	£37,147		£7,974	£34,728	£10,394
First-line treatment†		£19,138	£14,053		£5,085	£15,952	£3,186
First-line adverse events		£960	£2,003		−£1,043	£1,129	−£169
First-line R-maintenance		£20,147	£17,349		£2,798	£14,376	£5,771
First-line monitoring		£4,876	£3,742		£1,134	£3,270	£1,607
PFS2		£11,546	£13,798		−£2,253	£15,354	−£3,808
PD		£6,786	£8,681		−£1,895	£8,451	−£1,665
Total		£63,453	£59,627		£3,826	£58,532	£4,921
Base-case results
	Total costs	Total LYG	Total QALYs	Incremental costs	Incremental LYG	Incremental QALYs	ICER (£/QALY)
B-R vs CHOP-R
B-R	£63,453	9.05	7.19	£3,826	0.85	0.73	£5,249
CHOP-R	£59,627	8.20	6.46	–	–	–	–
B-R vs CVP-R
B-R	£63,453	9.05	7.19	£4,921	0.72	0.61	£8,092
CVP-R	£58,532	8.32	6.58	–	–	–	–

*Includes adverse event costs in first line and maintenance.

†Includes administration costs.

B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP, cyclophosphamide, vincristine, and prednisone; ICER, incremental cost-effectiveness ratio; LYG, life years gained; PD, progressive disease; PFS, progression-free survival; QALY, quality-adjusted life year; R, rituximab; R-maintenance, rituximab maintenance.

Table 4. Results of sensitivity analyses.

			B-R		CHOP-R		CVP-R		B-R vs CHOP-R			B-R vs CVP-R
Scenario		Parameter	Costs	QALYs	Costs	QALYs	Costs	QALYs	ΔCosts	ΔQALY	ICER	ΔCosts	ΔQALY	ICER
Base-case			£63,453	7.19	£59,627	6.46	£58,532	6.58	£3,826	0.73	£5,249	£4,921	0.61	£8,092
Clinical parameters
1	Increasing the hazard of progression for CVP-R vs CHOP-R	HR PFS1 CVP-R vs CHOP-R (Federico et al.32)	£63,453	7.19	£59,627	6.46	£58,125	6.06	£3,826	0.73	£5,249	£5,328	1.13	£4,733
2	Length of treatment benefit (base-case lifetime)	80 months	£64,292	7.06	£59,627	6.46	£58,532	6.58	£4,665	0.60	£7,796	£5,760	0.48	£12,061
3/4	Impact of time cut-off for early relapse	−6 months	£63,625	7.21	£59,852	6.49	£58,701	6.59	£3,772	0.72	£5,254	£4,924	0.62	£7,955
		+6 months	£63,303	7.16	£59,436	6.43	£58,402	6.57	£3,867	0.74	£5,259	£4,902	0.59	£8,285
5/6	Age threshold used in treatment pathways	55 years	£62,899	7.21	£58,802	6.53	£58,804	6.48	£4,097	0.68	£6,007	£4,095	0.73	£5,627
		75 years	£64,139	7.17	£60,618	6.41	£58,177	6.66	£3,521	0.76	£4,616	£5,962	0.52	£11,518
7	No death as progression events in PFS1	OS1 = 0	£67,062	7.68	£63,038	6.93	£62,168	7.17	£4,024	0.75	£5,381	£4,894	0.52	£9,479
8	No clinical effect of R-maintenance	HRR-maint = 1.0	£63,180	6.72	£58,411	5.93	£57,672	6.25	£4,769	0.78	£6,082	£5,508	0.46	£11,890
Utility scores
9	Applying primary utility scores from Wild et al.28	Wild et al.28	£63,453	6.53	£59,627	5.66	£58,532	5.71	£3,826	0.87	£4,400	£4,921	0.82	£6,000
10	Impact of adverse event- related outcomes	no disutility	£63,453	7.20	£59,627	6.49	£58,532	6.59	£3,826	0.71	£5,381	£4,921	0.62	£7,995
Costs
11/12	Impact of third-line costs: lump sum cost applied at second line progression, by type of second line treatment	−20% all	£62,706	7.19	£58,662	6.46	£57,630	6.58	£4,044	0.73	£5,548	£5,076	0.61	£8,347
		+20% all	£64,200	7.19	£60,591	6.46	£59,434	6.58	£3,609	0.73	£4,950	£4,766	0.61	£7,837
13	Cost of adverse event	No cost	£62,493	7.19	£58,623	6.46	£57,403	6.58	£4,869	0.73	£6,680	£5,090	0.61	£8,370
14/15	Cost of monitoring	−20% all	£61,936	7.19	£58,178	6.46	£57,081	6.58	£3,757	0.73	£5,154	£4,854	0.61	£7,983
		+20% all	£64,970	7.19	£61,075	6.46	£59,983	6.58	£3,895	0.73	£5,344	£4,987	0.61	£8,201
Decision-maker parameters
16/17	Discount rates	{cDR, oDR} = {1.5%, 1.5%}	£68,446	8.76	£64,301	7.78	£62,986	7.92	£4,145	0.98	£4,218	£5,459	0.84	£6,525
		{cDR, oDR} = {0%, 3.5%}	£73,131	7.19	£68,616	6.46	£67,101	6.58	£4,514	0.73	£6,193	£6,029	0.61	£9,915
		{cDR, oDR} = {3.5%, 0%}	£63,453	10.36	£59,627	9.10	£58,532	9.27	£3,826	1.26	£3,046	£4,921	1.09	£4,531
Combined scenarios
18	Scenarios 1 and 8	Utility, HR PFS1 CVP-R vs CHOP-R	£63,453	6.53	£59,627	5.66	£58,125	5.14	£3,826	0.87	£4,400	£5,328	1.39	£3,825

ASCT, autologous stem cell transplant; B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP, cyclophosphamide, vincristine, and prednisone; DR, discount rate; HDT, high dose therapy; HR, hazard ratio; ICER, incremental cost-effectiveness ratio; PFS, progression-free survival; QALY, quality-adjusted life year; R, rituximab; R-maintenance, rituximab maintenance.

Figure 2. Results of probabilistic sensitivity analysis (1000 simulations). (A) Distribution of simulations on the cost-effectiveness plane. (B) Cost-effectiveness acceptability curve. B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP, cyclophosphamide, vincristine, and prednisone; QALY, quality-adjusted life year; R, rituximab.

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