Treatment Value of Second-generation Bcr-Abl1 TKIs Compared With Imatinib to Achieve Treatment-free Remission in Patients With Chronic Myeloid Leukemia: a Modelling Study

SUMMARY

Background

Achievement of a sustained deep molecular response in order to discontinue Bcr-Abl1 tyrosine kinase inhibitor therapy (treatment-free remission) has become a potential aim of therapy in chronic myeloid leukemia ( CML). With the availability of generic imatinib at a low price compared with the high prices of second generation TKIs (which may offer deep molecular response status at a higher and faster rate), an important question is the value of second generation TKIs as frontline therapy for this particular treatment endpoint.The study aim is to address the potential value of second generation TKIs used as frontline therapy in CML in relation to the probability of achieving sustained deep molecular response with second generation TKI compared with generic imatinib, and the associated cost of each modality.

Patients and Methods

We used a decision analytic model to assess the value of different TKI approaches from the payer’s perspective. Achievement of sustained deep molecular response after 5 years was estimated at 26% with imatinib and 44% with second generation TKIs. We also modeled more favorable scenarios of achievement of sustained deep molecular response rate after 5 years of second generation TKIs of 66%, 88%, and a near perfect rate of 99%. We used different price scenarios for generic imatinib in the United States (average price $35,000/year; lowest price $4,400/year), in Europe ($4,000/year), and in emerging nations ($2,100/year). We used the price of nilotinib in the United States in basecase analysis and explored a wide range of prices in sensitivity analyses. We also considered two societal willingness-to-pay thresholds, $50,000/quality-adjusted life-year (QALY) and $200,000/QALY.

Results

None of the scenarios showed a potential good treatment value for using second-generation TKIs, at the current prices of $150,000+/year, in the United States, or $30,000–50,000/year elsewhere, as frontline therapy to achieve sustained deep molecular response. For example, considering a scenario in the United States using second generation TKIs versus imatinib at a price of $4,400/year, with the potential benefit in favor of second generation TKI (willingness-to-pay $ 200,000/QALY; deep molecular response 0.66), the cost of second generation TKIs should be less than$25,000/year. Under the same conditions in emerging nations, with a price of generic imatinib of $2,100/year of therapy and a clinically more realistic sustained deep molecular response rate of 66% (willingness-to-pay $50,000/QALY) for second generation TKIs, their price should not exceed $10,000/year of therapy.

Conclusion

Considering the current prices of second generation TKIs and of generic imatinib under different pricing scenarios in the United States, developed nations, and emerging nations, second generation TKIs at the current prices do not offer a good value as frontline therapy in CML in order to achieve sustained deep molecular response and treatment-free remission.

INTRODUCTION

The development of the Bcr-Abl1 tyrosine kinase inhibitors (TKIs) has changed the natural history of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML), as well as the goals and approach to the treatment of the disease. Five TKIs are now approved by the Food and Drug Administration (FDA) for the management of CML. Imatinib, dasatinib, nilotinib, and bosutinib are approved for the frontline therapy of CML. ^1,2 These and ponatinib are approved for the treatment of CML after failure of prior therapies. ^{1, 2}

As of December 2018, all second and third generation TKIs are under patent protection. According to the Wholesale Acquisition Cost in the Red Book ³ (Table 1), the annual price of TKIs alone could exceed $200,000 for these newer agents. Imatinib has been available in the United States in generic formulations since February 2016. The nine available imatinib generics in the United States range in price from $4,400 to $82,000 per year of treatment (Table 1). In other countries, second generation TKIs cost less, in some instances a third to one-half of the cost in the United States, mostly due to negotiations between regulatory and health authorities and drug manufacturers and distributors. Outside the United States generic imatinib is priced at a range of $2,000–$8,000 per year of treatment, even when the source for many of them are the same manufacturers who make them available in the United States. ⁴ In some countries like India, multiple versions of generic imatinib are available at an annual price as low as $400 a year. The actual cost to produce a tablet of 400 mg imatinib is less than $1. ⁵ Despite the concerns about the quality of generics, the preliminary data from the United States and other countries suggest that the safety and efficacy is similar to that of the patented drug Gleevec. ^6–8

Table 1:

Annual Cost of Tyrosine Kinase Inhibitors with Approved Indication for CML

Product Name	Active Ingredient	Generic	Daily Dose	Annual cost, WAC	NDC	Manufacturer/Distributor
GLEEVEC	imatinib mesylate	No	400 mg	$121,469	00078-0649-30	NOVARTIS PHARMACEUTICALS CORP.
IMATINIB MESYLATE	imatinib mesylate	Yes	400 mg	$ 28,416	60505-2901-03	APOTEX CORP.
IMATINIB MESYLATE	imatinib mesylate	Yes	400 mg	$ 4,914	43598-0345-30	DR REDDY’S LABORATORIES, INC.
IMATINIB MESYLATE	imatinib mesylate	Yes	400 mg	$ 16,419	00054-0249-13	HIKMA PHARMACEUTICALS USA INC.
IMATINIB MESYLATE	imatinib mesylate	Yes	400 mg	$ 72,300	42292-0044-03	MYLAN INSTITUTIONAL, INC.
IMATINIB MESYLATE	imatinib mesylate	Yes	400 mg	$ 4,423	00378-2246-93	MYLAN PHARMACEUTICALS, INC.
IMATINIB MESYLATE	imatinib mesylate	Yes	400 mg	$ 41,759	16714-0705-01	NORTHSTAR RX LLC
IMATINIB MESYLATE	imatinib mesylate	Yes	400 mg	$ 28,416	47335-0475-83	SUN PHARMACEUTICALS INDUSTRIES,INC.
IMATINIB MESYLATE	imatinib mesylate	Yes	400 mg	$ 28,861	00093-7630-56	TEVA PHARMACEUTICALS USA
IMATINIB MESYLATE AVPAK	imatinib mesylate	Yes	400 mg	$ 82,628	50268-0427-12	AVKARE, INC.
SPRYCEL	dasatinib	No	100 mg	$232,417	00003-0852-22	BRISTOL-MYERS SQUIBB CO.
TASIGNA	nilotinib hydrochloride	No	300 mg twice daily	$152,814	00078-0592-87	NOVARTIS PHARMACEUTICALS CORP.
BOSULIF	bosutinib	No	400 mg	$170,590	00069-0193-01	PFIZER LABS
ICLUSIG	ponatinib hydrochloride	No	45 mg	$198,732	76189-0534-30	ARIAD PHARMACEUTICALS, INC.

Long-term follow-up studies have shown that the achievement of complete cytogenetic response is the only treatment-associated factor that predicts long-term overall survival improvement. ^{1, 2} Other early surrogate endpoints of outcome in CML, e.g. major molecular response, have been associated with differences in progression-free survival, but not in overall survival. This could probably be explained by the management of CML in current clinical practice; that is, with adequate monitoring of patients with CML while on treatment, inadequate responses can be identified opportunely and changes of therapy to the highly effective new generation TKIs implemented at first evidence of cytogenetic relapse, resulting in a reversal of the event and still prolonging overall survival.

The long-term follow-up studies from as many as 16 randomized trials comparing second generation TKIs to imatinib therapy have not shown differences in overall survival outcomes. ^9–11 In a recent pharmacoeconomic analysis, using second generation TKIs as frontline therapy instead of generic imatinib (assumed to cost less than 30% of the patented imatinib) was associated with an incremental cost-effectiveness ratio (ICER) of $883,000 per quality-adjusted life-years (QALY). ¹² In simple terms, ICER, quantified as cost per QALY, represents the additional amount of dollars spent on a new intervention to gain an additional year lived in perfect health. The ICER is then compared with a value of cost-effectiveness threshold, also known as the societal willingness-to-pay, to determine whether the new intervention is considered cost effective. The societal willingness-to-pay reflects the payer’s upper threshold to cover new treatments. In Britain and other developed nations, the societal willingness-to-pay for new treatments is 30–40,000 euros/QALY (about $50,000/QALY). In the United States, some health-care experts have argued for the need to define, and perhaps accept, higher ICER values. Still, the ICER reported in the cost-effectiveness study mentioned above is considerably higher than the most commonly accepted societal willingness-to-pay of $50,000/QALY^13,14 or even the $100,000/QALY threshold value promoted in the oncology literature. ^15–19 Based on this study, generic imatinib, which produces similar overall survival as other TKIs, would be the preferred approach for patients with CML.

Maturing studies have demonstrated that, among patients with CML who achieve a sustained deep molecular response, most frequently defined as BCR-ABL1 transcripts of ≤0.0032% in the International Scale (IS) for 2 years or more, discontinuation of treatment would result in long-term treatment-free remissions in approximately 40–60% of patients. ^20–25 In one recent study, Saussele and colleagues concluded that such an approach that aims at treatment discontinuation as a goal of therapy for patients with CML who received any TKIs and achieved a deep molecular response would save about 22 million euros in drug costs. ²⁵ Over 90% of patients in that study had imatinib as first line therapy. Thus, the cost-saving suggested in the analysis by Saussele is not applicable to a treatment strategy using second generation TKIs as frontline therapy, because of the differences in the prices and the difference in the rate of sustained deep molecular response with second-generation TKIs and with imatinib. Because of the cost and long-term toxicities of TKIs, some CML experts have advocated for the possible value of using second generation TKIs as frontline CML therapy, particularly among patients with high-risk Sokal scores (in whom the benefit of second generation TKI appears to be greatest compared with imatinib), and among younger patients with CML (e.g. less than 50 or 60 years) in whom treatment discontinuation would be particularly important.

As the achievement of a treatment-free remission status in CML may be the goal of therapy for some CML experts, treating physicians, and patients, new therapies such as second generation TKIs that yield a higher of sustained deep molecular response are attractive options for frontline therapy. However, the substantially higher price of these new agents compared with generic imatinib raises the question of whether the additional amount of resources required to achieve such a deep molecular response status, perhaps faster and in more patients with second generation TKIs, is justifiable both clinically and financially.

The purpose of our analysis is to answer this question by comparing the cost-effectiveness of two frontline strategies: generic imatinib versus second generation TKIs.

METHODS

Study Design, Data Sources and Choice of Model. We used a decision tree to illustrate our research question. The choice to use a simply decision analytical model, instead of more elaborate models such as Markov models, is for the ease of communication of clinical audience. As show in Figure 1, the decision was to select either generic imatinib or a second generation TKI as the frontline therapy for patients who had chronic phase CML. Among these patients, some would achieve a deep molecular response after 5 years of treatment and among those, some would be in the state of sustained durable molecular response for at least two years and therefore would discontinue treatment as per NCCN guidelines. The model differentiated the clinical benefit of second generation TKIs compared with imatinib using the proportion of patients who achieved a sustained deep molecular response by the end of year 5: 44% with second generation TKIs and 26% with imatinib, based on data from the ENESTnd trial. ¹⁰ For patients who did not achievedeep molecular response, or who achieved deep molecular response but did not sustain it for at least 2 years, or who attempted treatment-free remission but relapsed and resumed therapy, they would continue TKI treatment for long-term use until the end of the observation period (i.e., 10 years). The choice of 10-year time period for the model was because studies published to date only extended to 10 years. To reflect patients’ preference toward treatment discontinuation with treatment-free remission, the model also assigned a higher utility value to treatment-free remission than to a remission with continued therapy. Costs associated with each frontline therapy included medication costs of TKIs and follow-up visits to monitor patients’ status adapted to whether the patient discontinued therapy or not. We modeled the frequency of follow-up visits according to the surveillance protocol in the European stop TKI (EURO-SKI) trial, with monthly visits for the first 6 months after TKI discontinuation, then every 6 weeks until month 12, then every 3 months afterwards. ²⁰ The study employed payers’ perspective; therefore, only included direct medical costs. All costs were expressed in 2018 US dollars. Both costs and QALYs were discounted at 3% per annum. All analyses were performed using TreeAgee 2018 R1.1 (Williamstown, MA), a decision analysis software.

Figure 1.

Frontline Therapy of Patients with Chronic Phase CML

TKI=tyrosine kinase inhibitor;

DMR = deep molecular response; TFR=treatment-free remission

0.26 or 26% represents the estimated incidence of sustained DMR at 5 years with imatinib. 0.44 or 44% represents the estimated incidence of sustained DMR at 5 years with second generation TKIs. 0.5 or 50% represents the estimated incidence of remaining in TRF after discontinuing TKIs

Given the wide range of costs of generic imatinib and of second generation TKIs shown in Table 1, we used the average cost in the US of generic imatinib and nilotinib (300 mg twice daily), and the lowest-cost second generation TKI ($152,814/year), in the basecase analysis. We chose using generic imatinib instead of patented imatinib (Gleevec) because generic imatinib is as effective and significantly less expensive than patented imatinib. We explored the range of medication costs in sensitivity analyses. We assessed the cost-effectiveness of the strategy using second generation TKIs as frontline therapy (versus generic imatinib) by calculating the incremental cost-effectiveness ratio (ICER). We then conducted several 3-way sensitivity analyses to address our key research question: how good the second generation TKIs need to be to justify their high costs. In each set of analyses, we explored four different values of the rate of achieving sustained deep molecular response after 5 years of treatment with second generation TKIs: 0.44, 0.66, 0.88, and 0.99, representing the scenario of second generation TKI basecase (0.44), a 50% increase from basecase (0.66), a 100% increase from basecase (0.88), and a near perfect treatment (0.99), respectively. For each rate of sustained deep molecular response, we plotted the costs of second generation TKIs against a range of utility value for chronic phase CML. The examination of variations in the utility of chronic phrase CML was to capture the clinical benefit in terms of QALYs, which was driven by the difference in utility between the health state of treatment-free remission and chronic phase CML. Corresponding to each rate of sustained deep molecular response and a pre-selected annual cost of generic imatinib, the blue-shaded area in each graph in Figures 2–4 portrays combinations of costs and utility values for chronic phase CML that would make the second generation TKIs the cost-effective strategy for frontline therapy. Figures 2–4 each examines a pricing scenario of generic imatinib: $35,000/year (the average costs of all generic formulations in the US), $4,400/year (the lowest cost generic imatinib in the US), and $2,100/year (cost of generic imatinib in markets of developing countries such as India). ²⁶ To reflect differences in healthcare costs across countries, we obtained cost of follow-up visits from a World Health Organization (WHO) study that reported country-specific cost of office visits. ²⁷ Within each pricing scenario, we explored two threshold values of societal willingness-to-pay: $50,000/QALY versus $200,000/QALY. Detailed description of our model and the analytical method can be found in the Appendix.

Figure 2.

presents results from three-way sensitivity analysis when the annual cost of generic imatinib is $35,000 with four rates of deep molecular response for the second generation TKIs: basecase 0.44, a 50% improvement from basecase 0.66, a 100% improvement 0.88, and a near perfect treatment 0.99. Figure 2A and 2B corresponds to a cost-effectiveness threshold of $50,000 and $200,000 per QALY, respectively. Areas shaded in blue are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs cost-effective in the United States. Areas shaded in orange are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs not cost-effective in the United States.

Note: Fig. 2A and 2B present results from sensitivity analysis with four rates of deep molecular response for the second generation TKIs (basecase 0.44, a 50% improvement from basecase 0.66, a 100% improvement 0.88, and a near perfect treatment 0.99) at two cost-effectiveness thresholds ($50,000 and $200,000 per QALY) when the annual cost of generic imatinib is $35,000. Areas shaded in blue are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs cost-effective in the United States. Areas shaded in orange are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs not cost-effective in the United States.

Figure 4.

presents results from three-way sensitivity analysis when the annual cost of generic imatinib is $2,100 with four rates of deep molecular response for the second generation TKIs: basecase 0.44, a 50% improvement from basecase 0.66, a 100% improvement 0.88, and a near perfect treatment 0.99. Figure 4A and 4B corresponds to a cost-effectiveness threshold of $50,000 and $200,000 per QALY, respectively. Areas shaded in blue are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs cost-effective in emerging nations. Areas shaded in orange are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs not cost-effective in emerging nations.

Note: Fig. 4A and 4B present sensitivity analysis with four rates of deep molecular response for the second generation TKIs (basecase 0.44, a 50% improvement from basecase 0.66, a 100% improvement 0.88, and a near perfect treatment 0.99) at two cost-effectiveness thresholds ($50,000 and $200,000 per QALY) when the annual cost of generic imatinib is $2,100. Areas shaded in blue are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs cost-effective in emerging countries. Areas shaded in orange are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs not cost-effective.

RESULTS

Table 2 summarizes the modeling parameters and the corresponding data source. As shown, we obtained information on the majority of clinical parameters and health utility values from the literature. The cost of TKIs was based on the Whole Acquisition Cost in 2018 REDBOOK, and that of office visit for monitoring purposes was from Medicare Physician Fee Schedule obtained from the CMS. Since the clinical benefit of second generation TKIs would be captured by a higher proportion of patients achieving a sustaineddeep molecular response, and subsequently a higher proportion of patients achieving treatment-free remission, a difference in health utility between the health state of chronic phase CML versus treatment-free remission would further amplify the clinical advantage of second generation TKIs in terms of QALY.

Table 2:

Model Parameters

Model Parameters	Basecase	Source
Clinical
%deep molecular response, imatinib	0.26	Reference10
%deep molecular response, second generation TKI	0.44	Reference 10
% treatment-free remission	0.5	References 20 and 25
Health utility
Chronic phase	0.89	Reference 27
treatment-free remission	1.00	Assumption
Costs
Generic imatinib (annual)	$35,000	REDBOOK
Second generation TKIs (annual)	$152,814	REDBOOK
Office visit	$109.44*	Medicare Physician Fee Schedule

^*based on national non-facility payment amount of CPT 99214.

An interesting observation was that according to a multinational study of health preferences associated with CML ²⁸, health utility for patients with chronic phase CML responding to therapy in the US was rather high (around 0.89). However, even if we assumed that health utility for patients with CML achieving treatment-free remission were as good as individuals in perfect health (i.e., health utility = 1.0), the higher rate of sustained deep molecular response associated with second generation TKIs would only translate into moderate improvement in QALY. Indeed, the results from the basecase analysis showed a QALY improvement of 0.04 with a 10-year study timeframe. Even with the least expensive second generation TKIs (i.e., $152,814/year), it will cost an additional $917,056 in the 10-year time frame to achieve this rather moderate magnitude of QALY improvement. Putting these numbers in the context of ICER, which quantifies the additional costs required to gain one full year in perfect health, it will cost the society over $22 million dollars to achieve one QALY gain from replacing generic imatinib with second generation TKIs for frontline therapy (Table 3).

Table 3:

Basecase Cost-Effectiveness Analysis

	Mean Costs	Mean Effectiveness	Incremental Costs	Incremental Effectiveness	ICER
Generic imatinib	$289,305	7.88	−$917,056	0.04	$22,765,208
Second generation TKIs	$1,206,361	7.92

Note: ICER = incremental cost-effectiveness ratio.

Our first set of sensitivity analyses used the average annual costs of generic imatinib in the US market (i.e., $35,000) as the base of comparison. Figure 2 shows that even if the second generation TKIs yield almost perfect clinical outcomes (rate of sustained deep molecular response as high as 99%; health utility of the chronic phase CML substantially worse --lower than 0.10); these assumptions still do not justify the current price difference of these TKIs compared to generic imatinib. Even with the extreme scenario of having societal willingness-to-pay as high as $200,000/QALY, the utility for chronic phase CML as low as 0.10, and the rate of deep molecular response as high as 0.99 (Figure 2B), the annual price of second generation TKIs would need to be lower than $82,030/year to be a cost-effective frontline agent. Figures 3 and 4 show that if the cost of imatinib was lower, it becomes even more difficult to justify higher prices of second generation TKIs. At the extreme scenario explored above that was most favorable to these new agents, if the annual costs of generic imatinib was set at the lowest generic formulation marketed in the US (i.e., at $4,400 per year), the annual cost of second generation TKIs would need to be lower than $45,000 per year to be cost-effective (Figure 3B). If the cost of generic imatinib was as low as $2,100 per year, ²⁶ as the price is in many international markets, the highest annual cost justifiable for second generation TKIs at a societal willingness-to-pay of $200,000/QALY would be $42,500/year.

Figure 3.

presents results from three-way sensitivity analysis when the annual cost of generic imatinib is $4,400 with four rates of deep molecular response for the second generation TKIs: basecase 0.44, a 50% improvement from basecase 0.66, a 100% improvement 0.88, and a near perfect treatment 0.99. Figure 3A and 3B corresponds to a cost-effectiveness threshold of $50,000 and $200,000 per QALY, respectively. Areas shaded in blue are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs cost-effective in the United States. Areas shaded in orange are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs not cost-effective in the United States.

Note: Fig. 3A and 3B present results of sensitivity analysis with four rates of deep molecular response for the second generation TKIs (basecase 0.44, a 50% improvement from basecase 0.66, a 100% improvement 0.88, and a near perfect treatment 0.99) at two cost-effectiveness thresholds ($50,000 and $200,000 per QALY) when the annual cost of generic imatinib is $4,400. Areas shaded in blue are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs cost-effective in the United States. Areas shaded in orange are the combination of health utility value for chronic phase CML and annual costs of second generation TKIs that would make the second generation TKIs not cost-effective in the United States.

When considering the additional scenarios in Europe and in developing nations, we replaced the US-based office visit costs with estimates of visit costs from the WHO that were more in line with the healthcare cost structure in these countries. ²⁷ In Europe, considering a generic imatinib price of $4,000/year, a sustained deep molecular response rate of 0.66 for second generation TKI, a willingness-to-pay of $50,000/QALY, and maximized QALY improvement, the price of second generation TKI should not exceed $9,321/year. In emerging nations, under the same exact assumptions, but with a generic imatinib price of $2,100/year, the price of second generation TKI should not exceed $7,247/year. Considering the same above scenarios but with a perfect sustained deep molecular response rate of 0.99, the price of second generation TKIs should not exceed $14,674/year in Europe, and should not exceed $12,424/year in emerging nations. Table 4 shows different scenarios in the United States, Europe and emerging nations, with some scenarios created with more favorable outcomes with second generation TKIs.

Table 4.

Common Scenarios, and Scenarios Favoring second Generation Tyrosine kinase Inhibitors (TKIs), and Expected Highest Price of TKIs that Provide Good Value

Location	Generic imatinib price ($/year)	Second generation TKI current price ($/year)	5-yr deep molecular response rate* of second generation TKI	willingness-to-pay/year of therapy ($/QALY)	Highest price of second generation TKI that provides value ($/year)
US	35,000	153,000	0.44 (basecase)	50,000	38,685
US	35,000	153,000	0.44	200,000	44,951
US	4,400	153,000	0.44	50,000	6,665
US	4,400	153,000	0.44	200,000	12,931
Europe	4,000	40,000	0.44	50,000	6,258
Emerging Nations	2,100	30,000	0.44	50,000	4,284
US	35,000	153,000	0.66 (50% increase)	50,000	43,683
US	35,000	153,000	0.66	200,000	58,443
US	4,400	153,000	0.66	50,000	9,737
US	4,400	153,000	0.66	200,000	24,497
Europe	4,000	40,000	0.66	50,000	9,321
Emerging Nations	2,100	30,000	0.66	50,000	7,247
US	35,000	153,000	0.99 (near perfect)	50,000	52,418
US	35,000	153,000	0.99	200,000	82,026
US	4,400	153,000	0.99	50,000	15,107
US	4,400	153,000	0.99	200,000	44,715
Europe	4,000	40,000	0.99	50,000	14,674
Emerging Nations	2,100	30,000	0.99	50,000	12,424

^*5-year deep molecular response rate for generic imatinib fixed at 26%

+ all prices calculated based on health utility of 0.1 for chronic phase and 1.0 for treatment-free remission to maximize the QALY (favors second generation TKIs).

QALY=quality-adjusted life-years

DISCUSSION

Recent studies and discussions have emphasized the importance of achieving sustained treatment-free remissions as an acceptable new endpoint of therapy. Some CML experts have also discussed cost reductions related to discontinuation of therapy and achievement of treatment-free remissions. However, such analyses have not considered the total denominator of patients treated, and the differential cost of second generation TKIs versus generic imatinib to produce such sustained treatment-free remissions. In our analysis, we have made several assumptions concerning the cost of second generation TKIs and of generic imatinib in the United States, in Canada and Europe, and in emerging nations. At their current pricing level, our analysis indicates that none of the scenarios explored in our examinations supported the cost-effectiveness of using second generation TKIs as frontline therapy for patients with chronic phase CML. In every scenario considered, the cost of second generation TKIs was too high to justify the additional treatment-free remission achieved. We therefore conclude that, at the current prices, second generation TKIs do not provide a good “value” for achieving the endpoint of sustained deep molecular response and treatment-free remission. Even if one accepts societal willingness-to-pay of $200,000/QALY, which is considerably higher than currently accepted standards, and the most favorable conditions for second generation TKIs (utility improvement from chronic phase to treatment-free remission 0.9; rate of deep molecular response 0.99), which are unrealistic based on available data, to be a good treatment value, the prices of second generation TKIs should be less than $45,000/ year in the United States (generic price 4,400/year) and developed nations. The cost of second generation TKIs (under the same extremely favorable condition of QALY improvement and rate of deep molecular response 0.99) should not exceed $43,000/year of therapy in emerging nations where the cost of generic imatinib is $2,100/year of therapy (Figure 4B, panel 4). If we accept a more clinically realistic deep molecular response of 0.66, the cost of second generation TKI would be $22,100/year (Figure 4B, panel 2).

Our study has several limitations. One is the uncertainty surrounding the incidences of long-term infrequent side-effects and the cost of treating these side-effects in different geographic areas. Second generation TKIs are increasingly associated with serious though infrequent long-term toxicities. Some concerns are the occurrences of arterial-thrombotic events with nilotinib and dasatinib (cumulative rate 10–15% over 10 years), of pleural effusions and pulmonary hypertension with dasatinib, of gastrointestinal toxicities and renal dysfunction with bosutinib, and of the less common occurrences of worsening diabetes (nilotinib), hypertension, neurologic toxicities, pancreatitis, and other long-term serious toxicities. ^9–11The cost of such additional toxicities was not calculated in our analysis However, they certainly add to the cost of second generation TKIs and reduce their treatment value in general. While imatinib is also associated with chronic adverse events, these tend to be of lesser severity (perhaps with the exception of renal dysfunction which appears to be similar to that of bosutinib but greater than nilotinib and dasatinib) and require fewer interventions.

Another limitation is that, when considering scenarios in the United States versus in advanced and emerging nations, there are treatment and cost considerations which may not be accounted for by our current methods. These include variations in the prices of generic imatinib and second-generation TKIs, different agreements between governments and drug companies that may change important considerations in our methods, the potential approval of generic second generation TKIs, and the variability in costs as well as frequencies of monitoring. These may affect some of the results and conclusions. However such variations should not significantly alter the key message, that second-generation TKIs are too expensive as a treatment value directed at achievement of a treatment-free remission status in CML.

Ongoing discussions in CML revolve around when patients need to change therapy. As discussed earlier, the achievement of complete cytogenetic response is the only factor associated with differences in long-term overall survival. Achievement of a major molecular response is associated with differences in progression-free survival or disease-free survival. Achievement of sustained deep molecular response provides an opportunity for treatment discontinuation in order to achieve a possible treatment-free remission status. Therefore in our opinion, patients and treating oncologists need to consider changing TKI therapy only for loss of a complete cytogenetic response. Failure to achieve a major molecular response or a sustained deep molecular response are not reasons to consider changing TKI therapy.

An interesting side-observation is the wide range of generic imatinib prices in the United States (Table 1). In particular, the price of generic imatinib provided by Mylan Pharmaceuticals was $4,423/year, and by Mylan Institutional $72,300/year. These are two subsidiaries of the same company, Mylan, operating in the United States, and providing the same generic at a mind-blowing price difference (almost 20 times) in the same geography and markets, the United States.

Our analyses calculated the mean costs and mean effectiveness based on a simplified model that carried several assumptions discussed earlier. However, what we intended to express, through the thought exercise demonstrated by our proof-of-concept model, is our concern that the discussions on the treatment value of treatment-free remission in CML may have been so far driven, in many subtle forms, by parties that might profit from these strategies, namely the drug industry. We hope that our study will stimulate additional scientific and objective analyses to argue different points or strategies. We also hope these discussions will be objective and data-based, and will occur independently of financially-driven support or pressures, as may have occurred in the past.

RESEARCH IN CONTEXT.

Recent discussions have emphasized the importance of sustained durable molecular response, in order to achieve a treatment-free remission status, as an important endpoint in CML therapy. No previous studies have investigated the treatment value of generic imatinib compared with second generation tyrosine kinase inhibitors as frontline therapy in CML with the treatment endpoint being treatment-free remission. A worldwide search of the English literature using search terms of chronic myeloid leukemia, treatment value, sustained deep molecular response and treatment-free remission confirmed this.

Our study used a modelling approach to investigate the treatment value of CML drugs. We used different variables, depending on countries and geographic context, including the whole acquisition cost of generic imatinib and second generation tyrosine kinase inhibitors, different societal willingness-to-pay, and different treatment scenarios. We concluded that second generation TKIs at the current prices provide poor treatment value as frontline therapy of CML. The findings from this study will have a major impact on frontline therapy of CML, on the assessment of the value of treatment-free remission, on governmental and insurance policies and coverage of different tyrosine kinase inhibitors as frontline CML therapies, and on potentially lowering the cost of second generation tyrosine kinase inhibitors.