The introduction of imatinib mesylate, the first BCR::ABL1 tyrosine kinase inhibitor, as a treatment of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) changed the course of the disease from invariably fatal (without allogeneic stem cell transplantation [SCT]) to indolent, where most patients have a near-normal life span compared with an age-matched normal population.^1,2 The subsequent development of second-generation (dasatinib, bosutinib, nilotinib) and third-generation tyrosine kinase inhibitors (ponatinib, asciminib) helped address additional considerations.

The first was the achievement of a durable deep molecular response (DMR or MR4+; BCR::ABL1 transcripts on the International Scale [IS] < 0.01%) and the possibility of stopping tyrosine kinase inhibitor therapy to attempt a treatment-free remission status.^3,4 The second was to offer and improve on later-line therapies in CML resistance. Resistance in CML was defined as failure to achieve a good early molecular response (BCR::ABL1 transcripts [IS] < 10% after 6 months of therapy) or having BCR::ABL1 transcripts (IS) of more than 1% after a year or more of therapy.^5,6 The third was to have access to alternative tyrosine kinase inhibitor options in patients who develop toxicities.

The BCR::ABL1 tyrosine kinase inhibitors improved the 10-year CML-specific survival (counting deaths related to CML or its therapy) rate from less than 20% to 90+%.² The CML-related annual mortality rate decreased from between 10% and 20% to between 0.5% and 1%. The condition for achieving a near-normal life expectancy was that patients are treated and monitored optimally, are treatment-compliant, and tyrosine kinase inhibitor therapy is changed appropriately for instances of CML resistance or tyrosine kinase inhibitor toxicity.

Fadi G. Haddad, MD

Hagop M. Kantarjian, MD, FASCO

The efficacy, ease of delivery (daily oral drugs), and relatively low toxicity of tyrosine kinase inhibitors (compared with the previous standards of care, interferon-alpha and allogeneic SCT) encouraged CML experts, oncologists, and patients to attempt to reach the lowest possible molecular disease burden as early as possible and for an extended duration—that is a durable DMR—to have the best rates of survival and treatment-free remission. To promote optimal treatment of CML, groups of CML experts formulated management guidelines and recommendations, which were followed, often rigorously, in community practice.^5,6 Also, some management decisions might have been influenced by drug company–sponsored educational resources designed to encourage a change from imatinib to newer-generation tyrosine kinase inhibitors.

The experience and long-term follow-up results with tyrosine kinase inhibitors in CML over the past 20 years allow us today to reexamine the treatment value and benefit/risk potential of some of these accepted practices. These practices were detailed in previous publications and are discussed here.^7-9

Question of Dose for BCR::ABL1 Tyrosine Kinase Inhibitors

In the early days of cytotoxic chemotherapy research, drugs were investigated in phase II to III studies at dose schedules one level below the maximum tolerated dose (MTD) defined in phase I studies (expected to produce serious side effects in 25% or less of patients). This was reasonable since chemotherapy drugs were used generally for 3 to 12 months. The inauguration of the era of targeted therapy (beginning in 2000 with imatinib) introduced new questions.

As patients lived longer and continued daily therapy for years or indefinitely, new toxicities were unmasked that were not anticipated from the early MTD experience. This was notable with the BCR::ABL1 tyrosine kinase inhibitors and also with multiple other targeted therapies now used on a chronic basis. Thus, the concept of a drug optimal biologic dose emerged, with the intent to maintain the efficacy of the below-MTD dose schedule and to reduce toxicity. Current research aims to define the optimal biologic dose through rational assessment of preclinical data and drug levels in vivo. In CML, however, determination of the optimal biologic dose has been based on anecdotal experiences of tyrosine kinase inhibitor efficacy maintained after dose reductions for side effects.^7,8

Several BCR::ABL1 tyrosine kinase inhibitors have now been investigated at lower-dose schedules than the approved ones in front-line and later-line CML therapies.

At MD Anderson, studies using front-line dasatinib at 50 mg daily in mostly low- to intermediate-risk Sokal disease (see sidebar) showed equivalent efficacy and significantly lower toxicity compared with historical data from the same institution with dasatinib at 100 mg daily, the approved front-line dose.^10-12 In a Japanese study in older patients with CML (70+ years; median age, 77.5 years), dasatinib at 20 mg daily was reported to be reasonably effective. However, even with short follow-up (median, 12 months), treatment was already discontinued in 3 of 52 patients because of “failure.”¹³

In later-line therapy, ponatinib was investigated in a three-arm randomized trial using starting doses of 45 mg, 30 mg, or 15 mg daily, with the dose schedule reduced to 15 mg daily once a patient achieved BCR::ABL1 transcripts (IS) < 1% (MR2). The analysis reported a superior efficacy of ponatinib at 45 mg daily, particularly among patients with T315I-mutated CML, in relation to MR2 rates: 60% with 45 mg, 25% with 30 mg, and 10% with 15 mg. However, among patients with non–T315I-mutated CML, the response rates were 54% with 45 mg and between 41% and 44% with 15 to 30 mg.

Surprisingly, the 3-year survival rates were similar with the three dose schedules and in both T315I- and non–T315I-mutated CML. In T315I-mutated CML, the 3-year survival rate was 86% with 45 mg, 79% with 30 mg, and 85% with 15 mg. In non–T315I-mutated CML, the 3-year survival rate was 90% with 45 mg, 93% with 30 mg, and 94% with 15 mg. This suggests that although the ponatinib starting dose should be 45 mg daily in T315I-mutated CML, a dose of 15 to 30 mg may be good enough in non–T315I-mutated CML—and safer.^14,15

The use of bosutinib at a starting dose of 400 mg daily in front-line therapy and at 500 mg daily in later-line therapy may result in an unnecessarily high dropout rate because of the early, usually self-limited, gastrointestinal side effects (diarrhea) and possibly others such as liver dysfunction (elevation of liver enzymes) and renal dysfunction (creatinine elevation). To help reduce the dropout rate, investigators proposed to start bosutinib with a dose escalation.

In a study by Castagnetti and colleagues, 63 patients older than age 60 were treated with bosutinib as second-line therapy, starting at 200 mg daily for 2 weeks, 300 mg daily for 2.5 months, and then 300 to 400 mg daily, depending on molecular response. The 3-year major molecular response rate (MMR; BCR::ABL1 transcripts [IS] < 0.1%) was 78%, the MR4 rate was 54%, and the 3-year survival rate was 81%, with 57% of patients still on bosutinib therapy at 3 years.¹⁶

Among patients in a solid molecular response, there is usually a reluctance to reduce the tyrosine kinase inhibitor dose schedule, even in the face of actual or potential side effects. This is because of the notions that reducing the dose may compromise efficacy and that it is better to change to another tyrosine kinase inhibitor (at a full dose) when toxicities emerge. This may not be a good approach when a patient is in good molecular response or if the toxicity is dose-dependent, nonprohibitive, and manageable with a dose reduction. Changing to another tyrosine kinase inhibitor at a full dose could induce new toxicities and cross-intolerance as well as increases in the cost of care.

“BCR::ABL1 transcripts between 0.01% and 1% should not be a reason to change tyrosine kinase inhibitor therapy.”

— FADI G. HADDAD, MD, AND HAGOP M. KANTARJIAN, MD, FASCO

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In an analysis by Li and colleagues of 837 patients on tyrosine kinase inhibitor therapy who achieved MMR, 271 patients received a lower tyrosine kinase inhibitor dose after a median time of 31 months to MMR. The rates of MR4 (66% with full dose, 75% with low dose) and the 6-year outcome rates (progression-free survival rate of 99% with a full dose, 100% with a low dose) were similar.¹⁷ Similar results were reported by Stagno and colleagues with dose de-escalation of nilotinib after achievement of good molecular responses.¹⁸

In summary, lower-dose schedules of tyrosine kinase inhibitors may, in many situations, be as effective, less toxic, and less costly (with tyrosine kinase inhibitors such as dasatinib, nilotinib, bosutinib and imatinib—but not with ponatinib—which is the same price for the 45-, 30-, and 15-mg tablets) than the approved-dose schedules.

Are ELN/NCCN Response Milestones Still Valid Today?

The European LeukemiaNet (ELN) recommends the lack of early molecular response at 3 to 6 months as an indicator of treatment failure that may require a change in tyrosine kinase inhibitor.⁵ This recommendation was based mainly on a study by Marin and colleagues reporting that the lack of a 3-month early molecular response on imatinib therapy was associated with an 8-year overall survival rate of 57% compared with 93% with early molecular response.¹⁹This was before wide access to second-generation tyrosine kinase inhibitors, and patients may have been changed to the less expensive hydroxyurea or offered allogeneic SCT. Later experiences showed a different picture.

In the German trials of front-line imatinib-based therapy, the 10-year overall survival rate was 82% with no 3-month early molecular response vs 88% with a 3-month early molecular response, suggesting caution but not failure.^20,21 Similar results were reported by others.^22-24 Lack of achievement of early molecular response (BCR::ABL1 [IS] >10%) at 6 months on imatinib led in some cases to a switch to a second-generation tyrosine kinase inhibitor, but this did not improve overall survival.²¹ Following this pattern, lack of early molecular response at 3 or 6 months with a second-generation tyrosine kinase inhibitor would result in a change to a third-generation tyrosine kinase inhibitor, which would be significantly more toxic and expensive without proof of benefit. Fortunately, a 6-month early molecular response of more than 10% is infrequent with second-generation tyrosine kinase inhibitors (2%–5%).^12,25

“The aspiration today of achieving treatment-free remission at any cost may result in more harm than good.”

— FADI G. HADDAD, MD, AND HAGOP M. KANTARJIAN, MD, FASCO

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Failure to achieve a complete cytogenetic response or its equivalent (BCR::ABL1 transcripts [IS] > 1%) at 1 year and beyond is also considered tyrosine kinase inhibitor treatment resistance or failure by the ELN and the National Comprehensive Cancer Network (NCCN) and an indication to change tyrosine kinase inhibitor therapy.^5,6 The long-term follow-up studies showed clearly that BCR::ABL1 transcripts (IS) of more than 10% after 1 to 2 years of imatinib or another tyrosine kinase inhibitor were associated with a worse overall survival. However, this may not be the same dire situation in patients with BCR::ABL1 transcripts (IS) of 1% to 10%, particularly if CML-specific survival and the age of the patient are considered.^21,26,27 Among older patients, optimized tyrosine kinase inhibitor therapy may provide a better outcome than allogeneic SCT, which may cause considerable toxicities and mortality.

What About Responding Patients Who Have Not Achieved MMR or DMR?

A common practice today is to change tyrosine kinase inhibitor therapy for a patient on treatment for more than 1 year if the BCR::ABL1 transcripts (IS) are > 0.01% (no DMR) or > 0.1% (no MMR). This was based on the notions that deeper molecular responses are always better and that treatment-free remission is a goal to achieve at any cost. This practice may have been based on earlier CML studies and perhaps encouraged in reviews and educational forums, as well as by the drug industry, to promote changing therapy from imatinib to newer-generation tyrosine kinase inhibitors. This practice led to frequent molecular monitoring (every 3 months), often showing relatively minor variations in reported BCR::ABL1 transcript levels that confused many patients and oncologists and resulted in unnecessary and costly changes of tyrosine kinase inhibitor therapy for “lack of optimal response.”

In retrospect, this practice may have caused more harm than good: new toxicities from the tyrosine kinase inhibitor change; tyrosine kinase inhibitor cross-intolerances; increased cost of tyrosine kinase inhibitor; and similar results despite the change. Of note, BCR::ABL1 transcripts may vary by almost half a log in value, even in the same sample or in different samples by the same laboratory. Thus, many “increases” in molecular disease (eg, BCR::ABL1 transcripts [IS] from 0.15%–0.2%) may be insignificant and reflect a stable response rather than disease resistance, or they could be simple testing variations/errors.^28,29

To summarize, BCR::ABL1 transcripts (IS) between 0.01% and 1% should not be a reason to change tyrosine kinase inhibitor therapy. Continuing the same tyrosine kinase inhibitor may offer the best treatment value. In contrast, a consistent upward trend of BCR::ABL1 transcripts over time (6–12 months or longer) in a compliant patient might reasonably bring about a discussion of alternative tyrosine kinase inhibitor therapies.

What About the Goal of Achieving Treatment-Free Remission at Any Cost?

Unlike the legitimate and beneficial goal of normalizing survival in CML, the aspiration today of -achieving treatment-free remission at any cost may result in more harm than good. In a patient with BCR::ABL1 transcripts (IS) > 0.01% after 2+ years of therapy, changing the tyrosine kinase inhibitor to a more potent one may increase the chance of achieving DMR, but it has never been shown to increase the chance of achieving a treatment-free remission. The fact that it is emphasized today may be because of logical inferences (durable DMR obtained after multiple tyrosine kinase inhibitors = more frequent treatment-free remission), the same as previous inferences about early MMR being a surrogate endpoint for survival (did not turn to be true).^25,30-32

Advocating such approaches, often encouraged today in educational sessions, reviews, and the cancer media, and supported by the drug industry, would encourage switches to a more potent tyrosine kinase inhibitor or one with unknown long-term side effects (ponatinib, asciminib). This may again cause increased financial toxicity and serious side effects, without a benefit to patients.^33,34 The goal of achieving treatment-free remission at any cost remains investigational and should not be pursued aggressively in community practice.

Management of Tyrosine Kinase Inhibitor Intolerance or Toxicities

Failure of tyrosine kinase inhibitor therapy was popularized in the CML literature to include resistant disease as well as intolerance. This categorization started when imatinib was the only approved tyrosine kinase inhibitor, when reducing the dose for intolerance still raised concerns about decreased efficacy, and when studies of novel tyrosine kinase inhibitors included patients with CML resistance and intolerance. These two groups were considered for such trials because both needed a change of tyrosine kinase inhibitor therapy.

In the long-term follow-up studies, the incidence of CML resistance (BCR::ABL1 transcripts [IS] > 1% after 1+ year of therapy; loss of cytogenetic or hematologic response; transformation) is low, about 1% annually (10-year resistance rate, 10%; 10-year blastic transformation rate, 5.8% on front-line imatinib therapy).²⁰

Today, the term “failure” should be reserved for true CML resistance alone, as proposed originally by the ELN recommendations.⁵ Patients with tyrosine kinase inhibitor intolerance or toxicities should be evaluated the same way as those with toxicities on other cancer treatments. Dose reductions are the first and best course of therapy, and changes of tyrosine kinase inhibitors should be considered only if the toxicities are prohibitive. Dose reductions were discussed previously, and are reasonable, particularly in patients in good molecular response. Imatinib may be reduced from 400 mg daily to between 100 and 300 mg daily. Dasatinib may be reduced from between 50 and 100 mg daily to between 20 and 50 mg daily. Bosutinib dose adjustment may occur early to avoid unnecessary discontinuations, and doses may be reduced from between 400 and 500 mg daily to between 100 and 300 mg daily. Nilotinib may be reduced from between 300 and 400 mg twice daily to between 150 and 200 mg twice daily or even to between 150 and 200 mg daily.

Prohibitive toxicities are those that are serious or may cause irreversible organ damage. They include recurrent pleural effusions, even on a lower dose of dasatinib or other tyrosine kinase inhibitors (more common with dasatinib; less so with bosutinib, though cross-intolerance may occur; best to use nilotinib or imatinib); pulmonary hypertension (usually with dasatinib); arterial or venous vaso-occlusive events (usually with ponatinib or nilotinib; safest tyrosine kinase inhibitor would be imatinib or bosutinib); persistent renal dysfunction even after lowering the tyrosine kinase inhibitor dose (usually with bosutinib or imatinib; switch to nilotinib or dasatinib); severe or rare neurotoxicity (dementia-like, parkinsonism); and immune-mediated pneumonitis, myopericarditis, hepatitis, or nephritis (any tyrosine kinase inhibitor; rare). In such instances, a change is advisable, and the tyrosine kinase inhibitor dose should be adjusted according to the response: For a patient in good molecular response, a lower dose is appropriate. For instance, for a patient in MMR with intolerance to imatinib and all three second-generation tyrosine kinase inhibitors, changing to ponatinib at 15 mg daily is better than using 30 to 45 mg daily of ponatinib or another agent.

Value of Tyrosine Kinase Inhibitors in Modern Practice

Oncologists and patients with cancer mostly were shielded from discussions of drug prices and cost of care until around 2000, when the development of novel targeted and immunotherapies ushered in the era of prohibitively high drug prices. Since 2012, oncologists have become more vocal about the resulting harm to patients.^35-41 Still, many cancer experts think this issue is best left to policymakers, who unfortunately may be influenced by the drug industry and its lobby.

As physicians sworn to “protect patients from harm and injustice,” it is important that we advocate against high cancer drug prices.⁴² In CML, the Surveillance, Epidemiology, and End Results data showed the estimated 5-year overall survival rate in the United States since 2000 is still 20+% below that in national studies in Europe, where 100% of patients have affordable access to tyrosine kinase inhibitors.⁴³ Also, both cancer experts and patients often find it difficult to navigate the intricacies of the U.S. health-care system (eg, prices of drugs, out-of-pocket expenses, restricted networks, and formularies). This is much simpler in Europe and in many countries with universal health-care systems and where health care is considered a human right, not a privilege.⁴⁴

“The price of brand tyrosine kinase inhibitors and other cancer drugs outside the United States is often as low as 20% to 50% of the price.”

— FADI G. HADDAD, MD, AND HAGOP M. KANTARJIAN, MD, FASCO

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Because of the healthy negotiations between the governments of different countries in Europe and elsewhere, and because $40,000 to $50,000/quality-adjusted life year is considered a good treatment value for an additional year lived with a new treatment compared with the standard of care, the price of brand tyrosine kinase inhibitors and other cancer drugs outside the United States is often as low as 20% to 50% of the price.³⁹ Outside the United States, the price of generic imatinib ranges from $300 to $5,000/yr. In the United States, because of distorted market forces, and despite the availability of 16+ generic formulations of imatinib, the acquisition wholesale cost (price when the drug leaves the manufacturer) decreased to an average of $5,000/yr.³⁶ However, because of the multiple intermediaries (wholesalers, hospitals, pharmacies, group purchasing organizations), the average wholesale price (price paid by the patient) remains about $130,000/yr.^36,38

New U.S. companies such as Mark Cuban Cost Plus and others now offer generic imatinib directly to patients at cost plus 15% profit, or less than $450/yr for imatinib at 400 mg daily. This is available and affordable to 100% of U.S. patients with CML. Generic dasatinib is available outside the United States for $3,000 to $10,000/yr and should be available in the United States next year. Generic formulations of bosutinib, nilotinib, and ponatinib should be available by 2027. Although generics alleviate the financial considerations outside the United States and simplify the goals of care (survival normalization, achievement of treatment-free remission, availability, and affordability to all patients), the picture will be more complex in the United States because of the average wholesale price and patient out-of-pocket expenses, until Cost Plus and similar companies offer them directly to patients, as was done with imatinib.

Keeping in mind these scenarios, how should physicians help patients with CML navigate the best tyrosine kinase inhibitor treatment value and achieve the three CML goals: normalization of life span, treatment-free remission, and affordability to all?

For front-line CML therapy, when survival normalization is the treatment goal, generic imatinib is the best treatment value. When treatment-free remission is the endpoint, generic dasatinib at 50 mg daily outside the United States and brand dasatinib at 50 mg daily in the United States (today) are good treatment options. Dasatinib at between 50 and 100 mg daily is a good front-line treatment option for patients with a high-risk Sokal score (see sidebar).

Among patients with tyrosine kinase inhibitor toxicities, reducing the tyrosine kinase inhibitor dose is the first best option if toxicities are nonprohibitive. For prohibitive toxicities, changing the tyrosine kinase inhibitor (from imatinib to second-generation agents; rotating second-generation agents if cross-intolerance) is appropriate. The tyrosine kinase inhibitor dose should be adjusted to the molecular response at the time the tyrosine kinase inhibitor is changed (lower doses if good molecular response). If ponatinib is considered after intolerance to all four other tyrosine kinase inhibitors, the dose should be low, 15 mg daily, if the BCR::ABL1 transcripts (IS) are < 1%.

Among patients with CML resistance, the first choice depends on the presence of particular ABL1 kinase domain mutations. In the absence of a “guiding” mutation, dasatinib at between 50 and 100 mg daily is a reasonable second-line option after front-line imatinib resistance. In case of true resistance to a second-generation tyrosine kinase inhibitor, and barring any guiding mutations, rotating second-generation tyrosine kinase inhibitors results in low response rates, wasting time and resources. In younger patients, switching to ponatinib followed by allogeneic SCT is appropriate. In older patients, consideration of combining the most optimal tyrosine kinase inhibitor with additional agents (eg, hydroxyurea, low-dose cytarabine, hypomethylating agents, omacetaxine) is reasonable. The endpoint of therapy would not be achievement of a good molecular response but instead maintaining the closest-to-normal survival possible with a good quality of life.

Currently, neither of the two third-generation tyrosine kinase inhibitors, ponatinib (average wholesale price of $270,000/yr for 15, 30, or 45 mg daily) and asciminib (average wholesale price of $258,000/yr for 40 mg twice daily; $1.3 million/yr for 200 mg twice daily, the dose needed for T315I-mutated CML) provides good treatment value in CML.³⁶ Among patients with true resistance to second-generation tyrosine kinase inhibitors, allogeneic SCT is a highly curative one-time procedure that may cost as little as $20,000 outside the United States and about $200,000 to $500,000 in the United States. 

DISCLOSURE: This work is supported in part by the Charif Souki Cancer Research Grant. Dr. Haddad reported no conflicts of interest. Dr. Kantarjian has received research grants and honoraria from AbbVie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Daiichi Sankyo, Immunogen, Ipsen Biopharmaceuticals, Jazz, KAHR Medical, Labcorp, Novartis, Pfizer, Shenzhen Target Rx, Stemline, and Takeda.

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Dr. Haddad is Assistant Professor, Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston. Dr. Kantarjian is Professor and Chair in the Department of Leukemia and the Samsung Distinguished Leukemia Chair in Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston.

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