The introduction of the BCR::ABL1 tyrosine kinase inhibitors (TKIs) in 2000 changed the treatment landscape and outcome of patients with chronic myeloid leukemia (CML).¹ While undergoing TKI therapy, patients are now anticipated to have a near-normal life expectancy, if they can afford the treatment, are optimally managed, are compliant, and are salvaged with later-line TKI therapy if they manifest TKI resistance (defined as BCR::ABL1 transcripts on the International Scale [IS] >1% after >12 months of TKI therapy).^2–4 The 4 FDA-approved TKIs for frontline chronic phase CML (CML-CP) therapy are imatinib (first-generation TKI), dasatinib, nilotinib, and bosutinib (second-generation TKIs).^5–8 All can be used as later-line therapies depending on the reasons for changing (eg, resistance or intolerance, prior TKIs used, presence of ABL1 kinase domain mutations, patient comorbidities, cost). Ponatinib and asciminib are third-generation TKIs approved for patients who do not experience a response to prior second-line TKIs or those with T315I mutation.^9,10 This review discusses the approach to treatment of CML-CP in the era of the generic TKIs to quantify the treatment value, or cost/benefit ratio, of such strategies.

A Primer on the Price of the BCR::ABL1 TKIs

The first BCR::ABL1 TKI, imatinib, demonstrated remarkable efficacy and a favorable safety profile compared with the standards of care—interferon alpha and allogeneic stem cell transplantation (SCT)—justifying its widespread use and initial price of $26,400/year when it was introduced in 2000 (inflation-adjusted estimate $48,000/year in 2023). The initial proposed price was comparable to that of interferon and was estimated by the company to cover the costs of its research and development (originally funded by investigator-awarded grants from the National Institutes of Health) and generate generous profits.¹¹ However, by 2012, the price had increased to $120,000/year, even though the number of patients being treated was increasing (from 5,000 to 9,500 new cases per year between 2000 and 2020; mortality only 1% annually), with the CML prevalence in the United States increasing from 30,000 cases in 2000 to an estimated 120,000 to 150,000 cases between 2020 and 2030.¹² The price of brand imatinib increased further, to approximately $160,000/year by 2020, and newer-generation TKIs were all priced at a range of $200,000 to $300,000/year.^13–23

Imatinib lost its patent in July 2015, and generics became available outside the United States at a price range of $500 to $5,000/year.^17,24 In the United States, because of distorted market forces and even with the availability of 4 to 5 generics by 2020 and ≥15 generics today, the average annual price of imatinib decreased to only $5,000/year when leaving the manufacturer (wholesale acquisition cost [WAC]), but remained at approximately $132,000/year by the time it reached the patient (average wholesale price [AWP]) because of the profits added by the various intermediaries (eg, wholesalers, pharmacies, hospitals, group purchasing organizations, pharmacy benefit managers).^14,17 This is until the Mark Cuban Cost Plus Drug Company and similar organizations started offering generic imatinib directly to patients (with a prescription) (Table 1).¹⁷

Table 1.

Average Wholesale Price of BCR::ABL1 Tyrosine Kinase Inhibitors in 2023

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Generic dasatinib is available outside the United States and is expected to be available in the United States by 2024. Generic formulations of bosutinib and nilotinib are expected to become available in the United States by 2027. This would then fulfill the 3 key aims of TKI therapy in CML: (1) survival normalization; (2) achievement of a durable deep molecular response (DMR; BCR::ABL1 transcripts [IS] ≤0.01%; MR4+), which translates into a treatment-free remission (TFR) status in 40% to 80% of patients, depending on whether the DMR duration before TKI discontinuation is 1 year, 2 years, or ≥5 years^25,26; and (3) making the treatment available and affordable to 100% of patients with CML, hence the discussion of the treatment value of different TKIs.

Treatment of CML-CP in the Frontline Setting

The choice of frontline TKI depends on several factors: (1) the goal of CML therapy (survival vs treatment discontinuation; potentially linked to the patient’s age); (2) the cost and affordability of TKIs; and (3) the patient’s age and comorbidities. When overall survival (OS) is the endpoint of therapy, imatinib provides a good treatment value.^20,27 Cost Plus Drugs offers generic drugs at cost plus 15%; for instance, 1 month of imatinib at 400 mg daily costs $34.70 per month, or $416.40/year.¹⁷ For a patient aged ≥60 years and considering a life expectancy of approximately 80 years in the United States, an additional 20 to 30 years of therapy at today’s price would cost approximately $8,300 to $12,500. The survival benefit with imatinib is similar to that obtained with second-generation TKIs priced at >$200,000/year (Table 1).¹⁷ Multiple other generic companies (eg, Civica Rx, ScriptCo Pharmacy) are working on providing more affordable generics to the patients, which may further reduce costs.¹⁷ Today’s issues with such generic companies are that (1) they bill the patients directly, although the cost may still be lower than the out-of-pocket expenses for drugs covered by insurers; 2) the range of medications offered is limited; and (3) all drugs that are offered are generics. However, encouraging and publicizing these new sources of affordable drugs could result in such companies broadening the range of drugs offered, bypassing intermediaries to expand to brand drugs, and billing insurers. This would be a major disruption of the distorted market forces in the United States, normalizing them to the original free market/capitalistic intent, and lowering significantly the drug prices and cost of care in the United States, similar to the situation existing today in Europe, Canada, Australia, Japan, and the rest of the world.

A recent analysis of patients with CML in the SEER database reported a 5-year OS rate of 73%, approximately 15% to 20% lower than reported from national studies in countries with universal health care systems (Sweden, Germany, France) and from company-sponsored trials in which 100% of patients have continuous access to the TKIs. Survival was also worse among patients with lower income, suggesting reduced access to TKI therapy among those with poorer financial status.²⁸

With the availability of more and probably cheaper generics, all patients with newly diagnosed CML-CP should have access to TKI therapy. Hematologists and oncologists should take into consideration their patients’ financial means when selecting a TKI.

If TFR is the goal of therapy, and among patients presenting with high disease burden (high Sokal risk), second-generation TKIs may be the best frontline strategy.^20,21,27 Outside the United States, generic dasatinib 50 mg daily provides the best treatment value (discussed later). However, in the United States, the benefit of second-generation TKIs may be offset by their higher total cost. A good treatment value, based on the Institute for Clinical and Economic Review (ICER), should not exceed $50,000/year, and should in time not exceed $5,000/year as generic formulations are available.²¹ Generic versions of dasatinib, bosutinib, and nilotinib will make them a good treatment value as frontline therapy to nearly all patients with CML, whether the aim of therapy is OS or TFR. This will also create more incentive for providers and patients to favor second-generation TKIs in the frontline setting. Faster and earlier achievement of deeper molecular responses will prevent the rare occurrence of early lymphoid blastic transformation with imatinib (approximately 2%–5% in the first 2 years) and will allow patients to reach the goal of durable DMR 1 to 2 years earlier than with imatinib therapy. This will improve overall outcome, particularly in patients with high Sokal risk; reduce the cost of care; and reduce the potential occurrence of long-term toxicities.

However, as with the experience with imatinib generics in the United States, one cannot assume that the AWP of generic second-generation TKIs will fall to reasonable levels when 4 to 5 generics of each become available. Brand drug companies often maneuver to extend patent durations, which delays the availability of generics, and then when they are available, the intermediaries often intervene to keep the AWP inflated.¹⁴

Lowering TKI Doses to Reduce Cost and Improve Affordability

To improve the affordability and lower the cost and toxicities of TKIs, their dose schedules can be safely reduced without compromising efficacy. Studies have shown that, in newly diagnosed CML-CP (mostly not high-risk Sokal), dasatinib 50 mg daily was associated with high rates of major molecular response (MMR; BCR::ABL1 transcripts [IS] ≤0.1%) and DMR with a low incidence of adverse events.^29,30 In a propensity score matching analysis, dasatinib 50 mg daily was at least as effective as 100 mg daily with a better safety profile, probably due to fewer treatment interruptions.³¹ In a Japanese trial of older patients with newly diagnosed CML-CP, dasatinib 20 mg daily showed encouraging efficacy and safety profiles, although the risk of early failure was higher than expected with the higher doses of dasatinib. Dasatinib 20 mg daily may be worth considering in patients aged ≥70 years in whom a higher incidence of pulmonary toxicities is anticipated.³²

Other studies have reported similar observations with bosutinib, nilotinib, and ponatinib, where lower doses were associated with good efficacy, fewer toxicities, and lower cost.^33–39 In a retrospective analysis of the BFORE randomized trial of bosutinib versus imatinib in newly diagnosed CML-CP, 103 of the 268 patients treated with bosutinib had dose reductions from 400 mg to 300 mg (n=80) and 200 mg (n=23). Of them, 41 (42%) achieved their first complete cytogenetic response following dose reduction, and 40 (39%) achieved their first MMR following dose reduction. This strategy reduced the incidence of most adverse events.³³ Another study of bosutinib dose optimization in the second-line setting with elderly patients showed high response rates and a favorable safety profile when bosutinib was given in a stepwise approach (starting at 200 mg daily and increasing by 100 mg increments as tolerated).³⁴ In the OPTIC trial, a response-based dose-reduction strategy of ponatinib was evaluated in 283 patients with CML-CP resistant to ≥2 TKIs or with T315I mutation. Patients received ponatinib 45, 30, or 15 mg daily, with dose reduction to 15 mg daily once the BCR::ABL1 transcripts (IS) were ≤1%. This approach resulted in higher response rates with ponatinib 45 mg daily in patients with T315I-mutated CML, but similar response rates among the 3 dose levels in patients without the mutation. The 4-year OS rates of 86% to 88% were similar with the 3 dose levels across all CML subsets.³⁸ A pooled analysis from the PACE and OPTIC trials showed that adopting a dose-optimization strategy with ponatinib resulted in fewer adverse events and similar or better outcomes.³⁹

Dose-reduction strategies were also evaluated among patients in MMR. In one retrospective analysis, 298 cases (in 246 patients) of CML-CP with TKI dose de-escalation due to adverse events were analyzed: imatinib (n=90), dasatinib (n=88), nilotinib (n=81), and bosutinib (n=39). The dose of imatinib was reduced to 200 to 300 mg daily, dasatinib to ≤20 to 70 mg daily, nilotinib to ≤200 to 400 mg daily, and bosutinib to <200 to 300 mg daily.³⁶ After dose reduction, MMR was maintained in 274 (92%) cases. Of 204 patients in MR4 at the time of dose reduction, 171 (84%) maintained or deepened their molecular responses. Of 94 cases in MMR at the time of dose reduction, 51 (54%) had improved molecular response. Of 13 cases who lost MMR, 11 regained response at a median of 3 months from restarting either the same TKI (at a higher dose) or a different TKI. Seventy-six patients eventually discontinued the low-dose TKI; their 2-year TFR rate was 74%.³⁶ Another phase II study examined the role of TKI dose de-escalation before treatment discontinuation among 174 patients treated for ≥3 years, and with stable MMR or MR4 for ≥12 months. They received their initial TKI with 50% dose reduction for 12 months: imatinib 200 mg daily (n=148), dasatinib 50 mg daily (n=10), or nilotinib 200 mg twice daily (n=16). During the 12 months of dose de-escalation, 12 (7%) patients lost MMR but regained it within 4 months of resuming full-dose TKI. This strategy was associated with fewer adverse events (lethargy, diarrhea, rash, and nausea) after dose reduction.³⁵

When considering dose reductions, we should note that lower doses of some TKIs (imatinib, dasatinib, nilotinib, bosutinib) translate into lower costs (Table 1). The unfortunate exception is ponatinib, where the manufacturer decided to price 45-, 30-, and 15-mg tablets at the same annual price of $271,000. This exception should be remedied.

Whether using generic or brand formulations, physicians should consider tailoring the choice of TKI to the patients’ comorbidities.²⁷ Common adverse events observed with imatinib include fluid retention, periorbital edema, and bone and muscle aches. Dasatinib therapy is mostly associated with myelosuppression, pleural effusions, and rarely, pulmonary hypertension (1%–2%).^40,41 Nilotinib is associated with an increased risk of diabetes and dyslipidemia, and a higher incidence of arterial and venous occlusive events as reported after a follow-up of 10 years.^42,43 Bosutinib can result in gastrointestinal toxicities, mostly diarrhea, as well as hepatic and renal dysfunction.^44,45

The Two Causes of Treatment Failure in CML

Treatment failure can be due either to CML resistance or TKI intolerance. The rate of true CML resistance, defined as BCR::ABL1 transcripts (IS) >1% (loss of cytogenetic or hematologic response) or CML transformation, is approximately 10% at 10 years of treatment. TKI intolerance (toxicities) occurs in 15% to 25%.^{20,27,46–48} The most common reason for changing TKI therapy is toxicity, which occurs in 15% to 25% of patients at 10 years, depending on the physician and patient thresholds. The choice of second-line therapy and beyond depends on the previous TKIs used, the cause(s) of failure (resistance or intolerance), the presence of ABL1 kinase domain mutations, the patient’s comorbidities, and the cost of therapy.¹⁷

Management of TKI Intolerance/Toxicities

For this discussion, TKI cross-intolerance is defined as the occurrence of similar toxicities with different TKIs, or the occurrence of different toxicities more often in a patient with a TKI toxicity. In the past, TKI cross-intolerance was considered uncommon when changing TKIs because the agents had very different chemical structures, but recently the phenomenon has been clearly recognized. For example, a patient who develops pleural effusions on dasatinib may be at a higher risk of developing pleural effusions on bosutinib, but less so on imatinib or nilotinib. A patient who develops arterial occlusive events (AOEs) on nilotinib or ponatinib would be more likely to develop AOEs on dasatinib (100 mg daily), but less so on imatinib or bosutinib. In a recent analysis, Busque et al⁴⁹ showed that the primary driver for switching TKIs was intolerance in all lines of treatment. Overall, serial intolerance was 6.6 times more frequent than serial resistance, suggesting a class effect for intolerance in some patients (20 patients switched serially across all lines due to intolerance).

Physicians and patients favored changing TKIs when intolerance occurred, because they assumed that a lower dose would have a lower efficacy, hence the term “failure.” This notion was also favored in the original studies (the only TKI available was imatinib, thus the need to include patients with imatinib toxicities) and current studies of second- and newer-generation TKIs that lumped together the 2 conditions (resistance and intolerance). This concept that a lower dose would have a lower efficacy was also publicized by the pharmaceutical companies, eager to promote the use of newer-generation TKIs over imatinib. Today, we advocate separating the 2 “failure” conditions, failure-resistance and failure-toxicity, and restricting the term failure to true resistance. This is how it is defined in the European LeukemiaNet (ELN) recommendations⁵⁰ and NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CML.⁵¹

In patients with TKI intolerance, the dose should always be reduced before a change of therapy is considered, in the absence of a prohibitive toxicity. A proposed strategy is summarized in Table 2. The prohibitive toxicities include (1) recurrent (>1 episode despite dose reduction) pleural effusions (occurring primarily with dasatinib, less commonly with bosutinib); (2) pulmonary hypertension (usually secondary to dasatinib; reversible in some cases after treatment with sildenafil and steroids); (3) arterio-occlusive or vaso-occlusive events (more common with nilotinib and ponatinib); (4) pancreatitis (possible with all TKIs, but mostly seen with nilotinib and ponatinib); (5) severe hypertension with ponatinib not responsive to antihypertensive therapies; (6) enterocolitis with bosutinib; (7) neurotoxicity (including dementia-like condition, parkinsonism, and intracranial hypertension; rarely seen with imatinib and dasatinib; can be reversible after several weeks or months from treatment discontinuation); and (8) immune-mediated adverse events, such as pneumonitis, hepatitis, myocarditis, pericarditis, or nephritis.^27,52 Notably, the cost of treating adverse events resulting from the long-term use of newer-generation TKIs adds to the original price of the drug. This results in an incremental cost of care and a reduction in the treatment value of second- and third-generation TKIs.²¹

Table 2.

Management of TKI Intolerance or Toxicities in Patients With No Resistance

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In the era of generic TKIs, we recommend using second-generation TKIs in patients responding to treatment who have intolerance to frontline imatinib: generic dasatinib 20 to 50 mg outside the United States, and lower dose schedules of any second-generation TKI in the United States (generic dasatinib is expected to be available in the United States in 2024, and generic nilotinib and bosutinib in 2027). Patients with intolerance to frontline second-generation TKIs can be switched to an alternative second-generation TKI that has a better safety profile tailored to the patient’s comorbidities. Generic imatinib could also be considered as a second-line therapy in selected patients who discontinue frontline second-generation TKIs due to toxicity (but not resistance). In responding patients with intolerance to imatinib and all 3 second-generation TKIs (very uncommon), lower dose schedules of ponatinib (15 mg daily) or asciminib (lower dose schedules not studied yet) may be used. For treatment intolerance, and assuming the patient does not have resistant disease (BCR::ABL1 transcripts [IS] ≤1%), we favor starting the new TKI at a lower dose schedule.

Management of TKI Resistance

Management of TKI resistance is guided by the type of frontline TKI used and the presence or absence of ABL1 kinase domain mutations (Table 3). In patients who develop resistance to frontline imatinib, and in the absence of resistance ABL1 mutations, choosing a second-generation TKI (dasatinib, bosutinib, or nilotinib) depends on the patient’s comorbidities, as discussed earlier. In patients who develop resistance to frontline second-generation TKIs, treatment is tailored according to the ABL1 mutational profile. In the presence of a resistance mutation other than the T315I, it is feasible to switch to an alternative second-generation TKI to which the detected mutation is sensitive. In patients without a guiding mutation and who have CML resistance to a second-generation TKI, switching to a third-generation TKI is better than rotating second-generation TKIs due to the low response rates observed with this strategy.⁵³ In patients with no detectable ABL1 mutation, or in those with the T315I gatekeeper mutation, we recommend changing treatment to ponatinib. Ponatinib is approved by the FDA at a starting dose of 45 mg daily, and upon achieving BCR::ABL1 transcripts (IS) ≤1%, a dose reduction to 15 mg is recommended. However, based on data available from the OPTIC trial, we recommend a starting dose of 45 mg daily for T315I-mutated disease and 30 mg daily for non–T315I-mutated disease, with a subsequent dose reduction to 15 mg daily once BCR::ABL1 transcripts (IS) are ≤1%.⁵⁴ Patients with ponatinib resistance should be considered for allogeneic SCT.

Table 3.

Management of TKI Resistance

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Of note, the long-term follow-up results indicate that failure to achieve the ELN milestones (resistance) with imatinib do not appear to be associated with such a dire prognosis (as thought previously), and that the term “failure” may perhaps be replaced with “caution” and may not necessarily indicate a need to change TKI therapy.^47,48 Also, the prognosis of T315I-mutated CML is not that adverse when it occurs in chronic phase (5-year OS of 70% in CML-CP, 37% in accelerated phase, and 10% in blastic phase). In such instances, allogeneic SCT, a one-time procedure, may be as effective (and curative) and less costly than using third-generation TKIs.⁵⁵

Ponatinib and Asciminib: Third-Generation TKIs

Ponatinib is a third-generation TKI approved by the FDA for patients in whom ≥2 prior TKIs failed or those harboring the T315I mutation based on the results from the PACE trial showing improvement in the rates of major cytogenetic response.⁵⁶ However, ponatinib 45 mg daily was associated with a high rate of adverse events, in particular AOEs (15%–20%). Findings from the OPTIC dose-optimization trial showed that using ponatinib 30 mg daily and decreasing the dose to 15 mg daily once BCR::ABL1 transcripts (IS) ≤1% is as effective and significantly less toxic than ponatinib 45 mg daily; the higher dose is most useful in patients with T315I mutation.⁵⁴ Asciminib, a newer third-generation TKI was also approved by the FDA as third-line therapy and for T315I-mutated disease based on the results of ASCEMBL trial showing higher rates of MMR at 6 months (26% vs 13%) compared with bosutinib.¹⁰

Findings from the PACE and OPTIC trials showed 2-year OS rates of 85% and 91%, respectively, with ponatinib given to patients with CML-CP resistant to prior second-generation TKIs. With longer-term follow-up, the 5-year OS rate was 73%.^9,54,56 This highlights the improved survival with ponatinib compared with second-generation TKIs in patients with resistant CML-CP.^52,57–59 In contrast, with longer follow-up of the ASCEMBL trial in patients with CML-CP and ≥2 prior TKIs, no survival difference was noted between asciminib and bosutinib, with 2-year OS rates of 97% and 99%, respectively.⁶⁰

Treating patients with ponatinib or asciminib is expensive. The cost of ponatinib therapy is approximately $271,000/year regardless of the dose. The cost of asciminib therapy is approximately $290,000/year for patients without T315I mutation (40 mg twice a day) and $1,448,000/year for those with T315I mutation (200 mg twice a day). Therefore, the cost of their treatments is excessive, particularly for patients with T315I mutation. Compared with allogeneic SCT, neither ponatinib nor asciminib is a good treatment value. In a retrospective analysis of patients with T315I mutation, treatment with ponatinib and/or asciminib or allogeneic SCT was independently associated with improved OS.⁵⁵ Therefore, in patients with T315I mutation, ponatinib can be used for a short period as a bridge to allogeneic SCT followed by (if indicated based on BCR::ABL1 transcripts) maintenance therapy with either ponatinib or an alternative second-generation TKI. Compared with a cost of $270,000 to >$1,400,000/year for third-generation TKIs, a one-time allogeneic SCT procedure costs approximately $20,000 to $40,000 in some countries such as India, Egypt, and Mexico.^61,62 In the United States, a one-time allogeneic SCT costs $300,000 to $500,000.

Conclusions

With the current availability of highly affordable imatinib generics, and hopefully second-generation TKI generics soon, all patients with CML-CP should have access to affordable, highly effective, and safe treatments. Using generic second-generation TKIs at reduced doses (dasatinib 50 mg daily) may be as effective, less toxic, and less costly than at standard doses, possibly making them preferable to imatinib as frontline therapy. Physicians should carefully select the most affordable TKI based on the goals of treatment and the patient’s comorbidities. In later lines of therapies and following resistance to second-generation TKIs, we favor dose-adjusted ponatinib due to longer follow-up and lower cost compared with asciminib. Allogeneic SCT should be considered in patients in whom treatment with second-generation TKIs fails, those with no access to newer TKIs, those with T315I-mutated CML, and selected patients with poor compliance.