Appendix
Table 1Deterministic sensitivity analyses: nilotinib v. high-dose imatinib (HDI) for imatinib-resistant patients
Parameter / Base case / Sensitivity analysis / ICERBase case / n/a / n/a / nil. dominates
General
Discounting / 3.5% p.a. costs and benefits / 0% p.a. costs and benefits / nil. dominates
Effectiveness
Time in post-progression survival / 9.7 years HDI, 10.5 years nilotinib / nilotinib and HDI value equal to HDI / £113,861a
Dose intensity / HDI 92%, nilotinib 100% / HDI 100%, nilotinib 100% / nil. dominates
HDI 72%, nilotinib 80% (both reduced by 20%) / nil. dominates
Major cytogenetic response rates / Nilotinib 52.4% / Nilotinib 45.4% (lower 95% CI) / nil. dominates
Nilotinib 59.4% (upper 95% CI) / nil. dominates
HDI 44.0% / HDI 33.4% (lower 95% CI) / nil. dominates
HDI 54.6% (upper 95% CI) / £201,854a
HDI 24.1% (lowest estimate identified: Kantarjian et al. 2003) / £407
Nilotinib 52.4%, HDI 44% / Nilotinib 48.5%, HDI 52.4% / £121,575a
Overall survival HDI at 5 years / 0.675 / 0.575 (lower 95% CI) / nil. dominates
0.775 (lower 95% CI) / nil. dominates
Hazard ratio responders v.
non-responders / 0.370 (pooled mean) / 0.127 (lowest estimate identified: Kantarjian et al 2006) / nil. dominates
0.156 (lower 95% of pooled estimate) / nil. dominates
0.876 (upper 95% of pooled estimate) / nil. dominates
0.893 (highest estimate identified: Kantarjian et al. 2004) / nil. dominates
Time in AP and BC / 0.8 years AP, 1.1 years BC / Halve: 0.4 years AP, 0.5 years BC / nil. dominates
Double: 1.6 years AP, 2.2 years BC / nil. dominates
Age starting 2nd-line treatment / 56 years / 52 years / nil. dominates
60 years / nil. dominates
Costs
Progressionfree survival / nilotinib PFS probability at 1.58 years = 0.63 / 0.56 (lower 95% CI) / nil. dominates
0.69 (upper 95% CI) / nil. dominates
Equal to dasatinib PFS / £127,899
Equal to HD imatinib PFS / nil. dominates
HDI lambda = 0.22 / HDI lambda = 0.15 (lower 95% CI) / nil. dominates
HDI lambda = 0.30 (upper 95% CI) / £11,298
Premature discontinuation rate / 23.2% nilotinib, 14.8% HDI / 0% nilotinib, 0% HDI / nil. dominates
Time treatment stops for patients
who discontinue prematurely / 3 months / 1 month / nil. dominates
5 months / nil. dominates
Medical management costs / Halve all unit costs or frequencies of use / nil. dominates
Double all unit costs or frequencies of use / nil. dominates
3rd line treatment cost / £1,040 / month / Zero / nil. dominates
AE costs / None / (£279 per patient HDI, £238 nilotinib) Novartis assumption / nil. dominates
Health state utilities
CP on treatment / 0.85 for nilotinib and HDI / 0.76 nilotinib, 0.76 HDI (BMS 0.85 response, 0.68 no response) / nil. dominates
CP no treatment / 0.85 / 0.70 / nil. dominates
AP / 0.73 / 0.60 / nil. dominates
BC / 0.52 / 0.40 / nil. dominates
anilotinib is cheaper and gives lower QALYs compared to HDI; therefore ICER represents £s saved per QALY lost, and values above a given threshold would be considered to provide good value for money
Table 2Sensitivity analyses: dasatinib v. high-dose imatinib (HDI)for imatinib-resistant patients
Parameter / Base case / Sensitivity analysis / ICERBase case / n/a / n/a / £91,499
General Parameters
Discounting / 3.5% p.a. costs and benefits / 0% p.a. costs and benefits / £81,899
Effectiveness
Time in post-progression survival / 9.7 years HDI, 6.9 years dasatinib / dasatinib and HDI value equal to HDI / £43,174
Dose intensity / HDI 92%, dasatinib 100% / HDI 100%, dasatinib 100% / £77,530
HDI 72%, dasatinib 80%
(both reduced by 20%) / £67,599
Dasatinib clinical data / Shah et al (2008) / Kantarjian et al (2007) comparative study / £322,764
Hochhaus et al (2007) / £161,862
MCyR rates / Dasatinib 58.1% / Dasatinib 49.4% (lower 95% CI) / £213,713
Dasatinib 66.8% (upper 95% CI) / £62,450
Dasatinib 100% (maximum possible) / £34,474
HDI 44.0% / HDI 33.4% (lower 95% CI) / £59,734
HDI 54.6% (upper 95% CI) / £318,492
HDI 24.1% (lowest estimate identified: Kantarjian et al. 2003) / £48,332
Dasatinib 58.1%, HDI 44% / Dasatinib 53.2%, HDI 52.4% / £1,340,016
OS for HDI at 5 years / 0.675 / 0.575 (lower 95% CI) / £89,251
0.775 (lower 95% CI) / £106,036
Hazard ratio responders
v. nonresponders / 0.370 (pooled mean) / 0.127 (lowest estimate identified: Kantarjian et al 2006) / £57,446
0.156 (lower 95% of pooled estimate) / £60,534
0.876 (upper 95% of pooled estimate) / £559,519
0.893 (highest estimate identified: Kantarjian et al. 2004) / £651,700
Time in AP and BC / 0.8 years AP, 1.1 years BC / Halve: 0.4 years AP, 0.5 years BC / £92,312
Double: 1.6 years AP, 2.2 years BC / £90,028
Age starting 2nd-line treatment / 56 years / 52 years / £87,436
60 years / £96,213
Costs
Progressionfree survival / Dasatinib PFS probability at 2 years = 0.77 / 0.70 (lower 95% CI) / £46,664
0.84 (upper 95% CI) / £158,503
Equal to nilotinib PFS / das. dominates
Equal to HD imatinib PFS / das. dominates
HDI lambda = 0.22 / HDI lambda = 0.15 (lower 95% CI) / £39,804
HDI lambda = 0.30 (upper 95% CI) / £118,969
Premature discontinuation rate / 10.2% dasatinib, 14.8% HDI / 0% dasatinib, 0% HDI / £78,899
Time treatment stops for patients
who discontinue prematurely / 3 months / 1 month / £92,010
5 months / £90,973
Medical management costs / Halve all unit costs or frequencies of use / £88,315
Double all unit costs or frequencies of use / £97,867
3rd line treatment cost / £1,040 / month / Zero / £142,090
AE costs / None / £279 per patient HDI, £296 dasatinib (BMS assumption) / £91,527
Health state utilities
CP on treatment / 0.85 for dasatinib and HDI / 0.77 dasatinib, 0.76 HDI
(BMS 0.85 response, 0.68 no response) / £146,879
CP no treatment / 0.85 / 0.70 / £56,890
AP / 0.73 / 0.60 / £91,091
BC / 0.52 / 0.40 / £90,987
Table 3Sensitivity analyses: dasatinib v. interferon- for imatinib-intolerant patients
Parameter / Base case / Sensitivity analysis / ICERBase case / n/a / n/a / £82,619
General
Discounting / 3.5% p.a. costs and benefits / 0% p.a. costs and benefits / £72,156
Effectiveness
Time in post-progression survival / 8.7 years IFN, 3.8 years dasatinib / dasatinib & IFN value equal to IFN value / £54,335
Dose intensity / IFN 55.5%, dasatinib 100% / IFN 100%, dasatinib 100% / £76,901
Dasatinib clinical data / Shah et al (2008) / Hochhaus et al (2007) (NB patients took dasatinib at 140mg/d in this study) / £95,278
MCyR rates / Dasatinib 74.4% / Dasatinib 61.4% (lower 95% CI) / £101,738
Dasatinib 87.4% (upper 95% CI) / £70,430
Dasatinib 100% (maximum possible) / £62,249
IFN 22.1% / IFN 18.6% (lower 95% CI) / £78,883
IFN 25.5% (upper 95% CI) / £86,820
Overall survival HDI at 5 years / 0.675 / 0.575 (lower 95% CI) / £80,847
0.775 (lower 95% CI) / £93,636
Hazard ratio responders vs non-responders / 0.370 (pooled mean) / 0.127 (lowest estimate identified: Kantarjian et al 2006) / £54,491
0.156 (lower 95% of pooled estimate) / £57,261
0.876 (upper 95% of pooled estimate) / £300,258
0.893 (highest estimate identified: Kantarjian et al. 2004) / £323,776
Time in AP and BC / 0.8 years AP, 1.1 years BC / Halve: 0.4 years AP, 0.5 years BC / £83,209
Double: 1.6 years AP, 2.2 years BC / £81,469
Age starting 2nd-line treatment / 56 years / 52 years / £79,381
60 years / £86,566
Costs
Progressionfree survival / Dasatinib PFS probability at 2 years = 0.87 / 0.77 (lower 95% CI) / £58,948
0.97 (upper 95% CI) / £101,442
Dasatinib PFS equal to nilotinib PFS / £64,264
IFN PFS probability at 1.75 years = 0.71 / 0.63 (lower 95% CI) / £85,170
0.78 (upper 95% CI) / £78,417
Premature discontinuation rate / 10.2% dasatinib, 55.3% IFN / 0% dasatinib, 0% IFN / £75,405
Timetreatmentstopsforpatients
who discontinue prematurely / 3 months / 1 month / £82,947
5 months / £82,285
Medical management costs / Halve all unit costs or frequencies of use / £81,946
Double all unit costs or frequencies of use / £83,965
3rd line treatment cost / £1,040 / month / Zero / £103,819
Health state utilities
CP on treatment / 0.85 dasatinib, 0.71 IFN / 0.81 dasatinib, (BMS 0.85 response, 0.68 no response), 0.71 IFN / £96,499
CP no treatment / 0.85 / 0.70 / £65,836
AP / 0.73 / 0.60 / £82,289
BC / 0.52 / 0.40 / £82,205
Table 4Sensitivity analyses: nilotinib v. interferon-for imatinib-intolerant patients
Parameter / Base case / Sensitivity analysis / ICERBase case / n/a / n/a / £104,698
General
Discounting / 3.5% p.a. costs and benefits / 0% p.a. costs and benefits / £88,863
Effectiveness
Time in post-progression survival / 8.7 years IFN, 5.8 years nilotinib / nilotinib & IFN value equal to IFN value / £60,313
Dose intensity / IFN 55.5%, nilotinib 100% / IFN 100%, nilotinib 100% / £93,846
MCyR rates / Nilotinib 46.5% / Nilotinib 36.0% (lower 95% CI) / £150,683
Nilotinib 57.0% (upper 95% CI) / £82,034
Nilotinib 100% (maximum possible) / £48,132
IFN 22.1% / IFN 18.6% (lower 95% CI) / £95,730
IFN 25.5% (upper 95% CI) / £115,915
Overall survival HDI at 5 years / 0.675 / 0.575 (lower 95% CI) / £102,595
0.775 (lower 95% CI) / £117,441
Hazard ratio responders vs non-responders / 0.370 (pooled mean) / 0.127 (lowest estimate identified: Kantarjian et al 2006) / £69,906
0.156 (lower 95% of pooled estimate) / £73,485
0.876 (upper 95% of pooled estimate) / £292,414
0.893 (highest estimate identified: Kantarjian et al. 2004) / £306,842
Time in AP and BC / 0.8 years AP, 1.1 years BC / Halve: 0.4 years AP, 0.5 years BC / £105,419
Double: 1.6 years AP, 2.2 years BC / £103,292
Age starting 2nd-line treatment / 56 years / 52 years / £100,099
60 years / £110,273
Costs
Progressionfree survival / Nilotinib PFS probability at 1.59 years = 0.83 / 0.75 (lower 95% CI) / £72,771
0.91 (upper 95% CI) / £152,763
Nilotinib PFS = dasatinib PFS / £141,545
IFN PFS probability at 1.75 years = 0.71 / 0.63 (lower 95% CI) / £112,457
0.78 (upper 95% CI) / £92,576
Premature discontinuation rate / 23.2% nilotinib, 55.3% IFN / 0% nilotinib, 0% IFN / £95,255
Time treatment stops for patients
who discontinue prematurely / 3 months / 1 month / £105,174
5 months / £104,218
Medical management costs / Halve all unit costs or frequencies of use / £104,756
Double all unit costs or frequencies of use / £104,582
3rd line treatment cost / £1,040 / month / Zero / £130,539
Health state utilities
CP on treatment / 0.85 nilotinib, 0.71 IFN / 0.76 nilotinib, (BMS 0.85 response, 0.68 no response)
0.71 IFN / £177,667
CP no treatment / 0.85 / 0.70 / £79,878
AP / 0.73 / 0.60 / £104,315
BC / 0.52 / 0.40 / £104,217
Table 5. Patient characteristics in the treatment arms of trials relevant for the economic modelling of dasatinib and nilotinib
Nilotinib / Dasatinib / High-dose imatinib / Interferon-Reference / Kantarjian et al (2007)(1) / Shah et al (2008)(2) (100mg once daily arm only) / Jabbour et al (2009)(3)
(imatinib dose escalated patients only) / O’Brien et al (2003)(4)
(interferon- + cytarabine arm only)
Number of centres / 63 / 139 / Not reported / 177
Number of patients / 280 / 167 / 84 / 553
Median age / 58 / 56 / 54 / 51
Sex (% male) / 51% / 50% / Not reported / 56%
Imatinib failure / 31% intolerant, 69% resistant / 26% intolerant, 74% resistant / 100% resistant / n/a
Duration of CML (median) / 57 months / 55 months / 28 months / 2 months
BCR-ABL mutation / 42% / 34% / Not reported / Not reported
MCyR at baseline / ≥2.9% / 20% / 45% / n/a
CHR at baseline / 43% / 51% / 36% / n/a
Prior therapy / 25% cytarabine, 83% hydroxycarbamide, 66% interferon-
8%stem cell transplantation / 23% chemo, 52% interferon-
6%stem cell transplantation / 95% interferon- / n/a
Inclusion criteria / Patients with Ph+CML-CP aged at least 18 years, and had imatinib resistance or intolerance, adequate performance status (WHO Performance Score =2), and normal hepatic, renal, and cardiac functions. Patients with had imatinib-resistance had to have been treated with a dose of at least 600 mg/d for 3 months. / Patients at least 18 years of age with Ph+ CP-CML and primary or acquired hematologic resistance or intolerance to imatinib were enrolled. Patients were required to have less than 15% blasts in peripheral blood or bone marrow, less than 30% blasts and promyelocytes in peripheral blood or bone marrow, less than 20% basophils in peripheral blood, =100,000/µL platelets (or less if related to prior drug therapy), and no extramedullary involvement (except liver or spleen). Primary resistance to imatinib (400-800 mg/d) was defined as no decrease in WBC count after = 4 weeks of treatment, no complete hematologic response after 3 months, no MCyR after 6 months, and no complete cytogenetic response after 12 months. Acquired resistance was defined as loss of MCyR (= 30% absolute increase in the percentage of Ph+ metaphases), loss of molecular response (concomitant with a= 10% Ph+metaphases at cytogenetic analysis), evidence of a new mutation in the BCR-ABL kinase domain, or loss of a confirmed CHR (WBC count >10,000/µL on all assessments over at least a consecutive 2-week period). Intolerance to imatinib was defined as grade 3 or worse toxicity which led to discontinuation of therapy. Patients who tolerated 400 mg/d imatinib but who did not achieve a CCyR and subsequently did not tolerate doses of = 600 mg/d were considered to be resistant to imatinib. / Not reported / Patients
were eligible for the study if they were between
18 and 70 years of age and had received a diagnosis
of chronic-phase, Ph-positive CMLwithinsix months before study entry. Chronic phase was
defined by the presence of less than 15 percent
blasts, less than 20 percent basophils, and less than30 percent blasts plus promyelocytes in the peripheral
blood and marrow.
Patients had to have
been previously untreated for CML, with the exception
of hydroxyurea, anagrelide, or both. Levels ofliver aminotransferases, serum bilirubin, andserumcreatinine that were no higher than 1.5 times theupperlimit of the normal range were required.
Exclusion criteria / Patients in BC, or patients received treatment with imatinib for 7 days and with hydroxyurea for 2 days prior to nilotinib, were excluded. Potassium and magnesium levels had to be greater than or equal to the lower limit or normal or corrected to within normal range. Patients receiving concomitant medications known to prolong the QT interval or inhibit CYP3A4 were excluded if alternative treatments were not possible. Imatinib resistance was defined as failure to achieve CHR after 3 months, or loss of a hematologic or cytogenetic response at any time during treatment with imatinib. Entry criteria for imatinib intolerance included patients with intolerant symptoms (but who also had never achieved a major cytogenetic response with imatinib), and hematologic toxicity of grade 4 severity persisting for more than 7 days. Imatinib-intolerant patients who had previously demonstrated sensitivity to imatinib, as evidenced by a prior major cytogenetic response, were excluded from participation in the study. / Included but not limited to: treatment with imatinib, interferon alfa, cytarabine therapy, or any targeted small-molecule anticancer agent within 7 days of initiation; uncontrolled or significant cardiovascular disease; history of a significant bleeding disorder unrelated to CML; eligibility for immediate autologous or allogeneic stem-cell transplantation; or concurrent incurable malignancy other than CML. / Not reported / Patients were excluded if they
had extramedullary disease other than hepatosplenomegaly
or fewer than 100,000 plateletsper cubicmillimeter unrelated totherapy. The presence of other
cytogenetic abnormalities in addition to Ph didnotexclude patients from the study.
Womenwho were breast-feeding, pregnant, or ofchildbearing
potential without a negative pregnancytest werenot enrolled. Patients were excluded if their Eastern
Cooperative Oncology Group performance status
was 3 or higher (poor), they had other uncontrolled
serious medical conditions, they had received prior
chemotherapy or treatment with any investigational
agent, they had undergone hematopoietic-cell transplantation,
they had undergone major surgerywithinthe preceding four weeks, they were known to be
seropositive for thehumanimmunodeficiencyvirus(screening was not required), or they had a history of
another cancer within the previous five years, with
the exception of basal-cell carcinoma or cervical carcinoma
in situ.
Reference List
(1) Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007 Nov 15;110(10):3540-6.
(2) Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. Journal of Clinical Oncology 2008 Jul 1;26(19):3204-12.
(3) Jabbour E, Kantarjian HM, Jones D, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 2009;113(10):2154-60.
(4) O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348(11):994-1004.
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