Cost-effectiveness and budget impact analyses of tisagenlecleucel in adult patients with relapsed or refractory diffuse large B-cell lymphoma from Singapore’s private insurance payer’s perspective

Figures & data

Figure 1. Model framework depicting the decision tree for TIS arm and patient transition into 3 health states in the partition survival model. Abbreviations. PFS, progression-free survival; PD, progression disease; QALY, quality-adjusted life year; RD, Relapsed disease.

Table 1. Cost and resource utilization model inputs for TIS.

Costs	Utilization rate	Unit cost	Frequency	Total cost	Source
Leukapheresis cost (TIS)	100%	S$4,130	1	S$4,130	Clinician advice (S$4,100: Leukapheresis; S$30: Cryopreservation)
Bridging chemotherapy	61.68%	S$6,402.8	1	S$3,949.04	For drug cost & IV admin cost – published data from Singapore government^26. For dose and frequency – NCCN^38. For proportion of patients receiving bridging – JULIET trial*^12. Similar to salvage chemotherapy includes drug + admin cost for 1 cycle)
Lymphodepleting chemotherapy (TIS)	68.86%	S$2,198.8	1	S$1,514.2	The total includes drug cost, admin cost. The dosing schedule and number of doses are obtained from the JULIET trial*^12 For distribution of patients receiving, each regimen obtained from JULIET trial*^12 For cost of drug and admin: published data from Singapore government^26
TIS cost	68.86%	S$500,000	1	S$344,311.4	For cost: Novartis
Inpatient hospital (infused)	68.86%	S$1,393.2	16.44 days	S$15,770.6	For LOS of hospitalization: JULIET trial (LDC)^12 and SG proposed label Kymriah (post infusion)* For cost: published data from Singapore government^26. Starting from LDC to post infusion
Total ICU cost (infused) after infusion	68.86%	S$1,978.7	0.90 days	S$1,229.9	For LOS: JULIET trial*^12 For cost: published data from Singapore government^26
SCR cost (Non infused)	31.14%	21,711.3	1	S$6,760.4	For drug cost: published data from Singapore government^26 For dose and frequency: NCCN^38
Total admin cost (non-infused)	31.14%	S$3,900	1	S$1,214.37	For cost: published data from Singapore government^26
Inpatient hospital +  Radiotherapy (non-infused)	31.14% of total patients which are non-infused patients; For radiotherapy: 20%	S$1,393.2 per day S$1,500 for radiotherapy	4 days of hospitalization 5 times radiotherapy cost	S$7,408.1	For cost: published data from Singapore government^26 For duration: The duration is based on number of inpatient admission, which is equal to average number of cycles (based on NCCN)^38 and total hospitalization days is based on clinician input. For radiotherapy cost – clinical opinion
ICU for CRS	15.56% (68.86% of total patients and 22.6% of infused patients)	S$1,978.7	8.5 days	S$2,617.4	For rate of CRS and LOS in ICU: JULIET trial*^12 For cost of ICU: published data from Singapore government^26
Tocilizumab for CRS	15.56% (68.86% of total patients which are infused and 22.6% of infused patients)	S$1,772.2	1.08	S$297	For cost: published data from Singapore government^26 For dose and % with CRS: JULIET trial*^12
Tocilizumab for CRS (admin cost)	15.56% (68.86% of total patients which are infused and 22.6% of infused patients)	S$325	1.08	S$54.5	For cost: published data from Singapore government^26 For % with CRS: JULIET trial*^12
IVIg for B-cell aplasia	25.75% (68.86% of total patients which are infused and 37.39% of infused receive IVIg for B-cell aplasia)	S$233./3000 mg	4 doses	S$2,670.2	For proportion receiving IVIg and mean dose of IVIg from JULIET trial*^12. Based on clinician advice, 400 mg/kg every month is the dose, amounting to 11 vials based on pack size of 3000 mg. For cost: published data from Singapore government^26
IVIg admin.	25.75% (68.86% of total patients which are infused and 37.39% of infused patients)	S$325/admin	4 doses	S$338.6	For cost: published data from Singapore government^26
Subsequent allo-HSCT (infused)	3.74% (68.86% of total patients which are infused and 5.43% of infused patients)	S$158,742.2	1	S$5,931.5	For rate: Pooled JULIET + UPenn trial*^1225 The cost of allo-HSCT includes treatment cost, follow up cost and adverse event cost. For treatment cost of allo-HSCT: published data from Singapore government^26 (S$150,000). For follow up cost for 1 year post HSCT (S$8,825): Private cost – clinicians (converted to public cost)^# For adverse event %: Clinician input For adverse event cost (S$5,442): published data from Singapore government^26
Subsequent allo-HSCT (non-infused)	2.35% (31.14% of total patients which are non-infused and 7.55% of non-infused patients)	S$158,742.2	1	S$3,733.8	For rate:^32^,^33. The cost of allo-HSCT includes treatment cost, follow up cost and AE cost. For treatment cost of allo-HSCT: published data from Singapore government^26 (S$150,000). For follow up cost for 1 year post HSCT (S$8,825): Private cost – clinicians (converted to public cost)^# For adverse event %: Clinician input For adverse event cost (S$5,442): published data from Singapore government^26
Subsequent auto-HSCT (infused)	0.54% (68.86% of total patients which are infused and 0.78% of infused patients)	S$100,000	1	S$533.8	For rate: JULIET + UPenn trial*^1225 For cost: published data from Singapore government^26. The cost of auto-HSCT includes treatment cost only
Subsequent auto-HSCT (non-infused)	(6.61%) 31.14% of total patients which are non-infused and 21.22% of non-infused	S$100,000	1	S$6,608.4	For rate:^32^,^33 For cost: published data from Singapore government^26. The cost of auto-HSCT includes treatment cost only
Other serious AEs (infused)	68.86% of total patients which are infused	S$5,396.4	Multiple	S$3,716.1	For Rate: JULIET trial*^12 For cost: Private cost – clinicians (converted to public cost)^#
Other serious AEs (non-infused)	31.14%	S$3,081.4	Multiple	S$959.5	For rate:^39 For cost: Private cost – clinicians (converted to public cost)^#
Heath states costs
PFS					For the frequency of tests in PFS state at different years for TIS: JULIET trial*^12
Year1:				S$2,103.6
Year2:				S$549.6
Year 3–5:				S$312.2
Post year 5:				S$15.2
Progressive disease				S$7,636.4	Based on resource utilization from Purdum et al., 2019^40 and cost of hospitalization from published data from Singapore government^26. Assumed to be same for all comparators and TIS
Death				0
Terminal care cost one time				S$3,210.9	^41

Abbreviations. AE, adverse event; Allo, allogeneic; Auto, autologous; CRS, cytokine release syndrome; HSCT, hematopoietic autologous stem cell transplantation; ICU, intensive care unit; IV, intravenous; IVIg, intravenous immunoglobulin; LDC, lympho-depleting chemotherapy; LOS, length of stay; NCCN, National Comprehensive Cancer Network; PFS, progression-free survival; SCR, salvage chemotherapy regimen; SG, Singapore; TIS, tisagenlecleucel.

*JULIET trial:¹², Upenn trial:²⁵.

^#Public sector costs were converted to private sector costs and vice versa through application of a conversion factor of 2.18.

Table 2. Cost and resource utilization model inputs for SCR.

Costs	Utilization rate	Unit cost	Frequency	Total cost	Source
SCR cost	100%	S$21,711.3 (public) S$47,360.4 (private)	1	S$21,711.3 (public) S$47,360.4 (private)	For cost: published data from Singapore government^26, For dose and frequency: NCCN^38 To convert cost to private the coefficient factor was applied^#
Total admin cost	100%	S$3,900 (public) S$8,507.4 (private)	1	S$3,900 (public) S$8,507.4 (private)	For cost: published data from Singapore government^26 To convert cost to private the coefficient factor was applied^#
Inpatient hospital	100%	S$1,393.2 (public) S$3,039.1 (private)	4 inpatient admissions and 4 days/hospitalization	S$22,291.4 (public) S$48,625.8 (private)	For cost: published data from Singapore government^26 For duration: The duration is based on number of inpatient admission, which is equal to average number of cycles (based on NCCN)^38 and total hospitalization days is based on clinician input. To convert cost to private the coefficient factor was applied^#
Radiotherapy	20%	S$1,500 (public) S$3,272.1 (private)	5	S$1,500 (public) S$3,272.1 (private)	Clinical opinion, cost: public perspective To convert cost to private the coefficient factor was applied^#
Subsequent allo-HSCT	7.55%	S$158,742.2 (public) S$346,276.1 (private)	1	S$11,991.3 (public) S$26,157.5 (private)	For rate:^32^,^33. The cost of allo-HSCT includes treatment cost, follow up cost and AE cost. For treatment cost of allo-HSCT: published data from Singapore government^26 (S$150,000). For follow up cost for 1 year post HSCT (S$8,825): Private cost – clinicians (converted to public cost)^# For adverse event %: Clinician input For adverse event cost (S$5,442): published data from Singapore government^26 To convert cost to private the coefficient factor was applied^#
Subsequent auto-HSCT	21.22%	S$100,000 (public) S$218,137.4 (private)	1	S$21,223.0 (public) S$46,295.3 (private)	For rate:^32^,^33 For cost: published data from Singapore government^26. The cost of auto-HSCT includes treatment cost only To convert cost to private the coefficient factor was applied^#
Other serious AEs	100%	S$3,081.4 (public) S$6,721.6 (private)	Multiple	S$3,081.4 (public) S$6,721.6 (private)	For % of events:^39 For cost: Private cost – clinicians (converted to public cost)^# To convert cost to private the coefficient factor was applied^#
Heath states costs
PFS					For the frequency of tests in PFS state at different years for SCR: clinician advice^@ For cost of tests: Private cost – clinicians (converted to public cost)^#
Year1:				S$95.7 (public), S$208.8 (private)
Year2:				S$69.4 (public), S$151.3 (private)
Year 3-5:				S$43.0 (public); S$93.8 (private)
Post year 5:				S$30.5 (public); S$66.6 (private)
Progressive disease				S$7,636.4 (public) S$16,657.8 (private)	Based on resource utilization from Purdum et al., 2019^40 and cost of hospitalization from published data from Singapore government^26. Assumed to be same for all comparators and TIS To convert cost to private the coefficient factor was applied^#
Death				0
Terminal care cost one time				S$3,210.9 (public) S$7,004.2 (private)	^41 To convert cost to private the coefficient factor was applied^#

Abbreviations. AE, adverse event; Allo, allogeneic; Auto, autologous; HSCT, hematopoietic autologous stem cell transplantation; NCCN, National Comprehensive Cancer Network; PFS, progression-free survival; SCR, salvage chemotherapy regimen; TIS, tisagenlecleucel.

^#Public sector costs were converted to private sector costs and vice versa through application of a conversion factor of 2.18.

^@the EFS costs included various cost items, consultant visit, haematology panel, coagulation panel, chemistry panel, CSF, serum test, B and T cell test, ECG, bone marrow aspirate, bone marrow biopsy, echocardiogram, liver function test.

Table 3. Utility inputs.

Inputs	Utility/ disutility value	Duration	Source
PFS utility	0.90 (SE: 0.01)		^12^,^44
PD utility	0.82 (SE: 0.02)
Treatment disutility TIS (infused)	−0.15	16 days	Disutility^45; Duration^12 and SG Kymriah label. This is applied for 1 cycle
Treatment disutility SCR	−0.15	84 days	Disutility^45; Duration^38. This is applied for 3 cycle
ICU stay due to CRS	−0.90	8.5 days	CRS rate and duration of ICU stay^12
ICU stay not due to CRS	−0.90	0.9 days	Duration^12
Subsequent-HSCT TIS	−0.30/year	1 year	Disutility and duration^45; For proportion of patients^12. Same disutility for auto- and allo-HSCT.
Subsequent-HSCT SCR	−0.30/year	1 year	Disutility and duration^45; Proportion of patients^32^,^33. Same disutility for auto- and allo-HSCT

Abbreviations. CRS, cytokine release syndrome; HSCT, hematopoietic autologous stem cell transplantation; ICU, intensive care unit; PD, progressive disease; PFS, progression-free survival; SCR, salvage chemotherapy regimen; SE, standard error; SG, Singapore; TIS, tisagenlecleucel.

Figure 2. Detailed cost breakdown of TIS and SCR arm demonstrating the key cost drivers. Abbreviations. HSCT, hematopoietic autologous stem cell transplantation; PFS, progression-free survival; SCR, salvage chemotherapy regimen; TIS, tisagenlecleucel.

Table 4. Summary of cost and benefits of TIS vs. SCR with or without HSCT (base-case).

Outcome	TIS	SCR with or without HSCT	Incremental
LYs	6.4559	3.4995	2.96
PFS	5.3945	1.7715	3.623
PD	1.0614	1.7279	−0.6665
QALYs	5.6655	2.8905	2.78
PFS	4.86	1.59	3.26
PD	0.87	1.42	−0.55
Treatment & AEs disutilities	−0.0202	−0.03	0.0098
Subsequent-HSCT disutilities	−0.0397	−0.09	0.0503
Costs	S$517,651.5 (US$391,537)	S$526,128.1 (US$397,949)	(S$8,477) ((US$6412))
Cost/LY			Dominant
Cost/QALY			Dominant

Abbreviations. AEs, adverse events; HSCT, hematopoietic autologous stem cell transplantation; LY, life years; PD, progressive disease; PFS, progression-free survival; QALY, quality-adjusted life year; SCR, salvage chemotherapy regimen; TIS, tisagenlecleucel.

Figure 3. Tornado chart of TIS vs. SCR demonstrating the main input parameters to which the model is most sensitive (a) base-case (b) publicly managed patients (non-subsidized) (c) publicly managed patients (subsidized). Abbreviations. DSA, deterministic sensitivity analysis; HSCT, hematopoietic autologous stem cell transplantation; MAIC, match adjusted indirect comparison; NMB, net monetary benefit; OS, overall survival; PFS, progression-free survival; SCR, salvage chemotherapy regimen; SMR, standard mortality ratio; TIS, tisagenlecleucel.

Figure 4. Cost-effectiveness plane for TIS vs. SCR (a) base-case; (b) publicly managed patients (non-subsidized) (c) publicly managed patients (subsidized) and cost-effectiveness acceptability curve for TIS vs. SCR with or without HSCT (d) base-case; (e) publicly managed patients (non-subsidized) (f) publicly managed patients (subsidized). Abbreviations. HSCT, hematopoietic autologous stem cell transplantation; QALY, quality-adjusted life year; SCR, salvage chemotherapy regimen; TIS, tisagenlecleucel; WTP, willingness-to-pay.

Table 5. Scenario analysis results for TIS vs. SCR with or without HSCT (base-case).

Parameters	Incremental Cost	Incremental QALY	NMB
Base-case	−S$8,477	2.78	S$749,345
Health state utility –^50	−S$8,477	2.81	S$758,253
Costs
Alternative TIS HRU and safety source (real world study): JULIET trial data	S$844	2.77	S$739,119
Alternative TIS HRU and safety source (real world study):^13	−S$27,148	2.79	S$773,274
Alternative TIS HRU and safety source (real world study):^15	−S$26,813	2.79	S$772,892
Alternative cost for post progression^51	S$28,462	2.78	S$712,407
Alternative cost for post progression^52	−S$7,766	2.78	S$748,635
Alternative cost for post progression^53	S$17,152	2.78	S$723,717
Time horizon
Time horizon − 30 years	−S$6,939	2.63	S$708,714
Time horizon − 20 years	S$38,532	2.17	S$539,921
Alternative modeling scenarios
Alternate efficacy for SCR: SCHOLAR	−S$41,780	2.57	S$728,549
Efficacy per parametric functions (weighted AIC) during trial period	−S$4,846	2.73	S$733,518
Use MAIC adjusted curve instead of observed data for TIS OS extrapolation from month 0 till year 3	−S$27,981	2.44	S$679,711
Use JULIET trial data for efficacy estimation for TIS	−S$5,777	2.64	S$709,335
Assume 100% patients assigned to TIS receive infusion	S$119,444	4.02	S$953,665
Consider long-term DLBCL survival data for OS after 4 years (vs. 3 years) with MAIC approach for OS extrapolation after trial period and before year 5	−S$20,110	2.47	S$680,249
Consider long-term DLBCL survival data for OS after 4 years (vs. 3 years) with parametric function approach for OS extrapolation after trial period and before year 5	−S$14,662	2.55	S$694,654
Consider long-term DLBCL survival data for OS after 5 years (vs. 3 years) with MAIC approach for OS extrapolation after trial period and before year 5	−S$17,783	2.48	S$679,813
Consider long-term DLBCL survival data for OS after 5 years (vs. 3 years) with parametric function approach for OS extrapolation after trial period and before year 5	−S$25,658	2.36	S$656,834
Consider 0% HSCT rate for salvage chemotherapy	S$98,582	3.32	S$787,217
Consider 5% HSCT rate for salvage chemotherapy	S$76,341	3.21	S$779,823
Consider 10% HSCT rate for salvage chemotherapy	S$55,148	3.10	S$771,294
Consider 20% HSCT rate for salvage chemotherapy	S$15,675	2.87	S$751,077
Consider via l sharing	−S$5,001	2.78	S$745,870
Consider indirect cost	−S$39,525	2.78	S$780,394
Consider continuous use of IVIG until median time to B-cell recovery	S$9,335	2.78	S$731,534

Abbreviations. AIC, Akaike information criterion; DLBCL, diffuse large B-cell lymphoma; HRU, healthcare resource utilization; HSCT, hematopoietic autologous stem cell transplantation; IVIG, intravenous immunoglobulins; MAIC, match adjusted indirect comparison; NMB, net monetary benefit; OS, overall survival; QALY, quality-adjusted life year; SCR, salvage chemotherapy regimen; TIS, tisagenlecleucel.

Table 6. ICER for TIS vs. SCR with or without HSCT (publicly managed patients).

Outcome	TIS	SCR with or without HSCT	Incremental
Scenario 1: non-subsidized costs for both TIS and SCR treatment
LYs	6.4559	3.4995	2.96
QALYs	5.6655	2.8905	2.78
Discounted	S$517,651.5 (US$391,537)	S$241,191.2 (US$182,430)	S$276,460 (US$209,107)
Cost/LY			S$93,512 (US$70,730)
Cost/QALY			S$99,623 (US$75,352)
Scenario 2: 50% subsidized costs for SCR and non-subsidized costs for TIS treatment
LYs	6.4559	3.4995	2.96
QALYs	5.6655	2.8905	2.78
Discounted	S$490,682.4 (US$371,139)	S$120,595.6 (US$91,215)	S$370,087 (US$279,924)
Cost/LY			S$125,180 (US$94,683)
Cost/QALY			S$133,361 (US$100,871)

Abbreviations. HSCT, hematopoietic autologous stem cell transplantation; ICER, incremental cost-effectiveness ratio; LY, life years; QALY, quality-adjusted life year; SCR, salvage chemotherapy regimen; TIS, tisagenlecleucel.

Figure 5. Net and total budget impact of TIS from private payer’s perspective. Abbreviations. TIS, tisagenlecleucel.

Table 7. Budget impact sensitivity analyses results.

	Year 1	Year 2	Year 3	Year 4	Year 5
Base-case	S$847,797	S$1,695,593	S$1,983,173	S$2,543,390	S$3,391,187
Equal market share between TIS and SCR with or without HSCT	S$5,934,577	S$6,494,795	S$6,782,374	S$6,782,374	S$7,342,591
Public and private factor: 4	S$695,111	S$1,390,222	S$1,527,785	S$2,085,333	S$2,780,444
Public and private factor: 1	S$954,069	S$1,908,138	S$2,295,054	S$2,862,207	S$3,816,276
Off-label (lenalidomide and ibrutinib) as additional comparators	S$712,711	S$1,263,811	S$1,822,804	S$2,415,143	S$3,274,696
No subsequent-HSCT	S$934,686	S$1,869,371	S$2,253,229	S$2,804,057	S$3,738,743

Abbreviations. HSCT, hematopoietic autologous stem cell transplantation; SCR, salvage chemotherapy regimen; TIS, tisagenlecleucel.

Table 8. Segmentation analysis of QALYs and LYs gain over JULIET study time horizon (3-year cure-point) and beyond 3-years.

	TIS			SCR			Incremental
	First 3 years	3 years-lifetime	Total	First 3 years	3 Years-lifetime	Total	First 3 years	3 Years-lifetime	Total
LYs	1.4454	5.0105	6.4559	0.9286	2.5709	3.4995	0.5168	2.4397	2.96
QALYs	1.2019	4.4636	5.6655	0.6863	2.2042	2.8905	0.5156	2.2594	2.78

Abbreviations. LYs, life-years; QALYs, quality-adjusted life-years; SCR, salvage chemotherapy regimen; TIS, tisagenlecleucel.

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