CML

Navigating the Management of Chronic Phase CML in the Era of Generic BCR::ABL1 Tyrosine Kinase Inhibitors

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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

Table 1.VIEW TABLE

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 years25,26; 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

Table 2.VIEW TABLE

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

Table 3.VIEW TABLE

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.

BCR ABL Genetic Test

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What is a BCR-ABL genetic test?

A BCR-ABL genetic test looks for a genetic mutation (change) on a specific chromosome.

Chromosomes are the parts of your cells that contain your genes. Genes are parts of DNA passed down from your mother and father. They carry information that determines your unique traits, such as height and eye color.

People normally have 46 chromosomes, divided into 23 pairs, in each cell. One of each pair of chromosomes comes from your mother, and the other pair comes from your father.

BCR-ABL is a mutation that is formed by the combination of two genes, known as BCR and ABL. It’s sometimes called a fusion gene.

  • The BCR gene is normally on chromosome number 22.
  • The ABL gene is normally on chromosome number 9.
  • The BCR-ABL mutation happens when pieces of BCR and ABL genes break off and switch places.
  • The piece of chromosome 9 that breaks off includes part of the ABL gene. When this piece moves over to chromosome 22, part of the ABL gene attaches to the BCR gene. The merged gene is called the BCR-ABL fusion gene. 
  • The changed chromosome 22, which contains the BCR-ABL gene, is called the Philadelphia chromosome because that’s the city where researchers first discovered it.
  • The BCR-ABL gene is not the type of mutation that is inherited from your parents. It is a type of somatic mutation, which means you are not born with it. You get it later in life.

The BCR-ABL gene shows up in patients with certain types of leukemia, a cancer of the bone marrow and white blood cells. BCR-ABL is found in almost all patients with a type of leukemia called chronic myeloid leukemia (CML). Another name for CML is chronic myelogenous leukemia. Both names refer to the same disease.

The BCR-ABL gene is also found in some patients with a form of acute lymphoblastic leukemia (ALL) and rarely in patients with acute myelogenous leukemia (AML).

Certain cancer medicines are especially effective in treating leukemia patients with the BCR-ABL gene mutation. These medicines also have fewer side effects than other cancer treatments. The same medicines are not effective in treating different types of leukemia or other cancers.

Other names: BCR-ABL1, BCR-ABL1 fusion, Philadelphia chromosome

What is it used for?

A BCR-ABL test is most often used to diagnose or rule out chronic myeloid leukemia (CML) or a specific form of acute lymphoblastic leukemia (ALL) called Ph-positive ALL. Ph-positive means a Philadelphia chromosome was found. The test is not used to diagnose other types of leukemia.

The test may also be used to:

  • See if cancer treatment is effective.
  • See if a patient has developed a resistance to certain treatment. That means a treatment that used to be effective is no longer working.

Why do I need a BCR-ABL genetic test?

You may need a BCR-ABL test if you have symptoms of chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). These include:

  • Fatigue
  • Fever
  • Weight loss
  • Night sweats (excessive sweating while sleeping)
  • Joint or bone pain

Some people with CML or Ph-positive ALL have no symptoms, or very mild symptoms, especially in the early stages of the disease. So your health care provider may order this test if a complete blood count or other blood test showed results that were not normal. You should also let your provider know if you have any symptoms that concern you. CML and Ph-positive ALL are easier to treat when found early.

You may also need this test if you are currently being treated for CML or Ph-positive ALL. The test can help your provider see if your treatment is working.

What happens during a BCR-ABL genetic test?

A BCR-ABL test is usually a blood test or a procedure called a bone marrow aspiration and biopsy.

If you are getting a blood test, a health care professional will take a blood sample from a vein in your arm, using a small needle. After the needle is inserted, a small amount of blood will be collected into a test tube or vial. You may feel a little sting when the needle goes in or out. This usually takes less than five minutes.

If you are getting a bone marrow aspiration and biopsy, your procedure may include the following steps:

  • You’ll lie down on your side or your stomach, depending on which bone will be used for testing. Most bone marrow tests are taken from the hip bone.
  • Your body will be covered with cloth, so that only the area around the testing site is showing.
  • The site will be cleaned with an antiseptic.
  • You will get an injection of a numbing solution. It may sting.
  • Once the area is numb, the health care provider will take the sample. You will need to lie very still during the tests.
    • For a bone marrow aspiration, which is usually performed first, the health care provider will insert a needle through the bone and pull out bone marrow fluid and cells. You may feel a sharp but brief pain when the needle is inserted.
    • For a bone marrow biopsy, the health care provider will use a special tool that twists into the bone to take out a sample of bone marrow tissue. You may feel some pressure on the site while the sample is being taken.
  • It takes about 10 minutes to perform both tests.
  • After the test, the health care provider will cover the site with a bandage.
  • Plan to have someone drive you home, since you may be given a sedative before the tests, which may make you drowsy.

Will I need to do anything to prepare for the test?

You usually don’t need any special preparations for a blood or bone marrow test.

Are there any risks to the test?

There is very little risk to having a blood test. You may have slight pain or bruising at the spot where the needle was put in, but most symptoms go away quickly.

After a bone marrow test, you may feel stiff or sore at the injection site. This usually goes away in a few days. Your health care provider may recommend or prescribe a pain reliever to help.

What do the results mean?

If your results show you have the BCR-ABL gene, as well as an abnormal amount of white blood cells, you will probably be diagnosed with chronic myeloid leukemia (CML) or Ph-positive, acute lymphoblastic leukemia (ALL).

If you are currently being treated for CML or Ph-positive ALL, your results may show:

  • The amount of BCR-ABL in your blood or bone marrow is increasing. This may mean your treatment is not working and/or you’ve become resistant to a certain treatment.
  • The amount of BCR-ABL in your blood or bone marrow is decreasing. This may mean your treatment is working.
  • The amount of BCR-ABL in your blood or bone marrow has not increased or decreased. This may mean your disease is stable.

If you have questions about your results, talk to your health care provider.

Learn more about laboratory tests, reference ranges, and understanding results.

Is there anything else I need to know about a BCR-ABL genetic test?

Treatments for chronic myeloid leukemia (CML) and Ph-positive, acute lymphoblastic leukemia (ALL) have been successful in patients with these forms of leukemia. It’s important to see your health care provider regularly to make sure your treatments continue to work. If you become resistant to treatment, your provider may recommend other types of cancer therapy.

Safely Stopping TKIs in CML

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In 1998, patients diagnosed with chronic myeloid leukemia (CML) had only about a 30% chance of surviving for 5 or more years – unless, that is, they were enrolled in the early clinical trials of imatinib (Gleevec), the first monoclonal antibody targeted against a tyrosine kinase.

Now, though, imatinib and its successor tyrosine kinase inhibitors (TKIs) are mainstays of treatment for CML and other hematologic and soft-tissue malignancies. A multicenter study published in 2011 looking at clinical outcomes among patients with CML treated with imatinib showed that among those who remained in complete cytologic remission 2 years after starting on the drug, survival was not statistically different from that of the general population.

More recently, investigators in the EURO-SKI (European Stop Tyrosine Kinase Inhibitor) study showed that while many patients with CML are maintained on TKIs indefinitely, it may be safe for some to stop or interrupt therapy with little fear of relapse or refractory disease recurrence if relapse does occur.

At the European Hematology Association 2016 annual congress, in Copenhagen, Denmark, Johan Richter, MD, PhD, professor in the division of molecular medicine and gene therapy at Lund University in Sweden, reported during the presidential session that among 750 patients with CML treated with a TKI who had been in remission for at least 1 year, nearly two-thirds (62%) of patients were able to maintain a treatment response 6 months after stopping the drug, and 56% retained responses 1 year after stopping TKI therapy.

The evidence suggests that patients with CML in deep molecular remission (MR4.0 or better according to European LeukemiaNet molecular response criteria) may be good candidates for interrupting TKI therapy, Richter said.

EURO-SKI Details

EURO-SKI investigators enrolled 868 adults with chronic-phase CML at 61 sites in 11 countries. The patients were required to have had at least 3 years of TKI therapy and to have been in deep molecular remission for at least 1 year before study entry. Patients for whom TKI therapy had previously failed were not eligible for the study.

A total of 750 patients had sufficient follow-up data — defined as a minimum of 6 months — for the analysis presented at the meeting. Of this group, 94% had been treated with imatinib as first-line therapy, 4% had received first-line nilotinib (Tasigna), and 2% had received first-line dasatinib (Sprycel). In total, 115 patients had switched to a second-line agent due to not being able to tolerate the first-line drug — 58 from intolerance to dasatinib, seven from intolerance to imatinib, and 49 for intolerance to nilotinib (data on one patient switched to another agent were missing).

The median duration of deep molecular remission before stopping a TKI was 4.7 years. The median time from diagnosis was 7.7 years, and the median duration of therapy was 7.6 years.

For the primary endpoint of molecular relapse-free survival, 62% of patients remained in remission for at least 6 months after stopping the TKI, 56% remained in remission at 12 months, 52% remained at 24 months, and 49% were still in deep molecular remission at 36 months.

The median time to restarting therapy for patients who resumed taking their TKI was 4.1 months.

Prognostic Factors Examined

 To evaluate potential factors that could be prognostic for relapse after treatment interruption, the investigators analyzed data on 448 patients treated with imatinib. Univariate analysis found that the only significant predictors of molecular remission status at 6 months were the duration of molecular response before stopping and the duration of imatinib therapy. Each additional year of imatinib treatment was associated with a 16% increase in the likelihood that a patient would remain in deep molecular remission for 6 months after stopping (odds ratio 1.16).

Neither age, gender, depth of molecular response, nor standard CML risk scores were associated with remission status after stopping imatinib.

To determine a cutoff point beyond which it may be safe to stop a TKI, the investigators used a minimal P-value approach, and found a cutoff of approximately 6 years of imatinib therapy. This cutoff was based on a molecular relapse-free survival at 6 months of 65.5% for patients who remained on imatinib for more than 5.8 years, versus 42.6% for those who had been on imatinib for 5.8 years or less.

As of the most recent follow-up, more than 80% of patients who had a loss of their deep molecular remissions after stopping a TKI regained remission after re-starting therapy, Richter reported, and patients who were sensitive to TKIs retained their sensitivity after stopping and restarting therapy.

Sunitinib Maintenance After Chemotherapy Improves Progression-Free Survival for Extensive-Stage Small Cell Lung Cancer.

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After standard chemotherapy, maintenance therapy with sunitinib delayed relapse by approximately 1.5 months compared with placebo for patients with extensive-stage small cell lung cancer (SCLC), according to new findings from a phase II trial.

Dr. Neil Ready, MD, PhD, of the Duke Cancer Institute in Durham, North Carolina, presented results from the randomized, phase II Cancer and Leukemia Group B (CALGB) 30504 trial (Ready N et al., 2013) at the 2013 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois.

Sunitinib is an oral, multitargeted receptor tyrosine kinase (RTK) inhibitor that shows potent and selective activity against vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and other molecular targets implicated in tumor growth and angiogenesis. Sunitinib is currently approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor. Although sunitinib and other RTK inhibitors have been studied extensively in non-small cell lung cancer (NSCLC) (Gridelli C et al.), few studies have examined sunitinib in SCLC.

CALGB 30504 Study Design

The CALGB 30504 trial began in 2007 as a phase I trial of concurrent therapy with sunitinib and standard chemotherapy in untreated extensive-stage SCLC. The concurrent regimen was not feasible, however, due to the risk of grade 5 neutropenia (Ready N et al., 2010). In 2008, the CALGB 30504 protocol was amended to a randomized phase II trial designed to evaluate maintenance sunitinib following chemotherapy. In the current analysis, 85 patients received 4-6 cycles of standard-dose chemotherapy with cisplatin/etoposide or carboplatin/etoposide every 21 days. Patients were randomly assigned to maintenance therapy with sunitinib 37.5 mg/day (n = 44) or placebo (n = 41) until disease progression. Crossover to sunitinib maintenance was permitted in the placebo arm at disease progression.

The median patient age was 60 years (range, 39-77 years). The majority of patients (76.5%) completed 6 cycles of chemotherapy; 26% received cisplatin and 74% received carboplatin. Among patients with a complete or partial response (n = 78), 34 patients (44%) received prophylactic cranial irradiation 4 to 6 weeks after completing chemotherapy.

Patients completed a median of two cycles of maintenance therapy (range, one to 17 cycles). In the sunitinib arm, 68% of patients completed 1 to 4 cycles, while 23% completed 5 to 8 cycles. Four patients (9%) completed 9 or more cycles of sunitinib maintenance. The crossover rate was high, with 40% of patients in the placebo group initiating sunitinib following disease progression.

Improved Progression-Free Survival

The CALGB 30504 trial met its primary endpoint of improved progression-free survival after chemotherapy with maintenance sunitinib. The median progression-free survival was 3.77 months in the sunitinib maintenance group, compared with 2.30 months in the placebo group (HR, 1.53; P = 0.037).

Despite the high crossover rate, maintenance sunitinib showed a trend toward improved overall survival compared with placebo. The median overall survival was 8.95 months in the sunitinib group and 6.89 months in the placebo arm (HR, 1.17; P = 0.27).

Evidence of Single-Agent Activity

An analysis of tumor size before and after crossover to sunitinib in six patients with disease progression in the placebo group also demonstrated the single-agent antitumor activity of sunitinib. In the 6 to 12 weeks prior to crossover, the tumors were exhibiting rapid growth. Following crossover to sunitinib, tumor growth slowed in each case, and some tumors decreased in size.

In another case, the pattern of tumor response during chemotherapy and maintenance provided additional support for single-agent activity with sunitinib. The patient showed a partial response to chemotherapy, which plateaued between cycles 4 and 6, but converted to a complete response during sunitinib maintenance. The complete response was maintained without progression for 15 cycles (45 weeks) of maintenance therapy.

Safety Findings

Maintenance sunitinib appeared safe and feasible at this dose. During maintenance, 46.5% of patients in the sunitinib group reported at least 1 grade 3/4 adverse event, compared with 19.5% of patients in the placebo group. The most common grade 3/4 adverse events during sunitinib maintenance were fatigue (19%), neutropenia (14%), leukopenia (7%), thrombocytopenia (7%), and hyponatremia (5%). Grade 4 events included gastrointestinal hemorrhage (n = 1) and pancreatitis (n = 1).

Next Steps

A biomarker analysis of blood samples is being planned, with the goal of identifying prognostic and predictive markers that may guide the selection of patients for maintenance therapy. A randomized phase III trial is being proposed to test the hypothesis that maintenance sunitinib after standard chemotherapy improves survival in patients with extensive-stage SCLC.

Dr. Ready explained the rationale for additional studies of maintenance sunitinib. “We felt that the [phase II] results were consistent with the hypothesis that there could be a 2-month or more improvement in overall survival with maintenance sunitinib in this setting. We feel that it is reasonable to consider a phase III trial to test that hypothesis,” Dr. Ready said.

Source: The oncologist

 

Current and Future Options for Targeting Activated Kinases in Acute and Chronic Leukemias

Contributors: Anna Azvolinsky, PhD, Anne Jacobson, MPH, CCMEP, CMPP

Tyrosine kinase oncogenes such as BCR-ABL and FLT3 are commonly mutated and activated in acute and chronic myeloid leukemias. The development of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myelogenous leukemia (CML) and provided new treatment options for patients with chronic myeloproliferative neoplasms and acute leukemias. In a special session at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting on the role of targeted therapy in acute and chronic leukemias, experts discussed the current clinical issues and future opportunities associated with the targeted inhibition of aberrant signaling pathways that drive the development and progression of these malignancies.

Chronic Myelogenous Leukemia

Resistance to BCR-ABL-targeted therapy in patients with CML arises through an array of potential mechanisms, ranging from non-specific multidrug resistance to inherent BCR-ABL genetic alterations. Michael J. Mauro, MDof the Knight Cancer Institute, Oregon Health & Science University, in Portland, Oregon, discussed targeted approaches to managing treatment resistance in patients with CML.

In 2001, the approval of imatinib, the BCR-ABL kinase inhibitor, launched a new area of targeted therapy for CML. Imatinib has been so successful that it has grown to become the targeted therapy all other therapies want to emulate—oncologists often aspire to finding the “imatinib” of other cancer types. As of 2013, five targeted agents are currently available for CML, including two agents, bosutinib and ponatinib, that joined the salvage treatment armamentarium in 2012.

After more than a decade of experience with imatinib in CML, the oncology community has gained critical insight about the development and progression of treatment resistance, with potential implications for other targeted therapies. Importantly, resistance to imatinib is a function both of time and disease volume. Early reduction of disease burden is associated with the reduction or elimination of unstable clones, leading to a reduction in the risk of relapse. Timely cytogenetic and molecular response is a strong predictor of functional cure, which is defined as the absence of meaningful proliferation even after treatment is stopped.

Options for patients who show early resistance to imatinib (e.g., BCR-ABL/ABL >10% at 3 months) include switching to another tyrosine kinase inhibitor based on mutational analysis, evaluating candidacy for stem cell transplant, or referring the patient to a clinical trial. Ongoing trials will evaluate the utility of various approaches to early resistance, including immediate versus delayed switch to an alternate targeted regimen. Treatment selection is further individualized based on a tolerability profile and likelihood of treatment adherence. Among current options, nilotinib, dasatinib, and bosutinib are proven salvage options with promising activity in the front-line setting. Ponatinib also represents a compelling salvage option, particularly for patients with heavily pretreated CML who have stopped responding to all other therapies. A phase III trial comparing ponatinib with imatinib in patients with newly diagnosed chronic-phase CML is currently underway.

Chronic Myeloproliferative Neoplasms

Targeted therapy is rapidly changing the treatment landscape for chronic myeloproliferative neoplasms, including primary myelofıbrosis (MF), essential thrombocytopenia (ET), and polycythemia vera (PV). Following the identification of the JAK2V617F mutation in 2005, the first JAK1/2-targeted therapy was approved just six years later, in 2011. Claire Harrison, DM of the NHS Foundation Trust in the UK, discussed the current standard of care for primary MF, post-ET/PV MF, and other myeloproliferative neoplasms in the era of JAK1/2 inhibitor therapy.

Ruxolitinib was the first oral, selective JAK1/2 inhibitor approved for the treatment of intermediate- and high-risk MF, based on substantial reduction in spleen size and improvements in other constitutional symptoms and quality of life in the phase III COMFORT-1 and COMFORT-2 trials. To date, treatment with ruxolitinib has not resulted in any molecular remissions, although there is hope for the concept of a ‘cure’ with targeted therapy alone. In current practice, allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with MF. Other limitations of current systemic treatment options in MF include concerns about the induction of leukemia as well as the inability to reduce late myeloid transformation.

Building on the success of ruxolitinib, other JAK-targeted inhibitors in development include SAR302503, a selective JAK2 inhibitor; pacritinib, an oral, once-daily, highly selective inhibitor of JAK2 and FMS-like tyrosine kinase 3 (FLT3); and CYT387, an oral JAK1/2 inhibitor. Future clinical trials in this setting may focus on regimens designed to improve the hematologic toxicity profile of current JAK1/2 inhibitor therapy or improve treatment efficacy via the use of novel JAK1/2 inhibitors alone or in combination with other targeted agents, such as histone deacetylase (HDAC), phosphatidylinositol 3 (PI3)-kinase, and smoothened pathway inhibitors.

Acute Leukemia

Advances in the molecular profiling of acute leukemia, particularly the role of activating mutations that result in signaling molecule alterations, may introduce new opportunities for targeted therapy. Neil Shah, MD, PhD of the University of California, San Francisco, discussed the evolving rationale for kinase inhibition in the treatment of acute leukemia.

Acute leukemia is frequently associated with activating mutations in signaling molecules. Kinase inhibitors provide an effective, well-tolerated tool to substantially reduce the burden of disease and, when combined with chemotherapy, improve cure rates in patients with acute myeloid leukemia (AML). The number of possible combination regimens with other targeted agents is growing as novel pathway inhibitors are being developed. Performing detailed molecular analyses of tumor samples is becoming more feasible, and promises to facilitate the personalized selection of rational targeted therapies and combination regimens in the near future.

Several kinase inhibitors are in development for AML, but early stage results lag behind the advances seen in the CML setting. Many of the targeted multikinase inhibitors currently under development in AML may have a role as bridge therapy, providing patients the time to transition to a potentially curative stem cell transplant.

The key obstacle in the development of targeted agents for AML is a lack of a known dominant driver mutation. The most common mutation appears to be a tandem repeats of the activating mutations of the FLT3 receptor tyrosine kinase in about a quarter of patients. Agents such as quizartinib and crenolanib are in clinical trials, but rapid relapse is common. “FLT3 may be a passenger rather than a driver mutation [in AML] and not worth targeting,” saidDr. Shah. Inhibitors of KIT, JAK2, mTOR, and MEK are also under evaluation in AML, but their potential antitumor activity in patients who do not harbor mutated kinases is unknown.

Incorporating next-generation molecular sequencing tools into studies of targeted therapeutics will advance the use of personalized treatment in acute leukemia. Continued participation of patients with AML and other malignancies in clinical trials is strongly encouraged, Dr. Shah said.

Source: The oncologist

 

 

 

 

 

 

 

 

 

FDA Approves New Drug to Treat Chronic Myelogenous Leukemia.

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The Food and Drug Administration has approved bosutinib (Bosulif) to treat chronic myelogenous leukemia (CML), a blood and bone marrow disease that usually affects older adults. Bosutinib is intended for patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive CML who are resistant to or who cannot tolerate other therapies, including imatinib (Gleevec).

Most people with CML have a chromosomal aberration called the Philadelphia chromosome, which causes the bone marrow to make an abnormal tyrosine kinase enzyme called Bcr-Abl. This enzyme promotes the proliferation of abnormal and unhealthy infection-fighting white blood cells called granulocytes. Bosutinib is a tyrosine kinase inhibitor (TKI) that works by blocking Bcr-Abl signaling.

Bosutinib’s safety and effectiveness were evaluated in a clinical trial involving 546 adults with chronic, accelerated, or blast phase CML. All of the patients had been previously treated with at least one TKI, either imatinib or imatinib followed by dasatinib (Sprycel) and/or nilotinib (Tasigna).

Among patients with chronic phase CML, 34 percent of patients who had been treated previously with imatinib and 27 percent of those who received more than one prior TKI achieved a major cytogenetic response within 24 weeks.

Among patients with accelerated phase CML who had received at least one prior TKI, 30 percent had their blood counts return to the normal range (a complete hematologic response) by week 48, and 55 percent achieved a complete hematologic response, no evidence of leukemia, or return to chronic phase (an overall hematologic response) by week 48. Among patients with blast phase CML who had received at least one prior TKI, 15 percent had a complete hematologic response and 28 percent an overall hematologic response by week 48.

The most common side effects observed in those receiving bosutinib were diarrhea, nausea, a low level of platelets in the blood, vomiting, abdominal pain, rash, anemia, fever, and fatigue.

Source: NCI

 

A Novel Mechanism in Chronic Lymphocytic Leukemia

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Mutations in SF3B1 lead to altered RNA splicing and contribute to CLL pathogenesis.

Chronic lymphocytic leukemia (CLL) is biologically and clinically heterogeneous, with some patients enjoying many years of treatment-free survival while others experience relentless disease progression. To better understand the molecular underpinnings of this heterogeneity, investigators performed massively parallel sequencing of paired tumor and germline DNA from 91 CLL patients. Acquired somatic mutations were identified by comparing whole genome and whole exome sequences from the tumor cell and normal DNA.

Recurring mutations were confirmed in four genes previously known to be associated with CLL: TP53, ATM, MYD88, and NOTCH1. Five additional genes with recurring mutations were also identified. The most common of these (found in 15% of cases) involved splicing factor 3b subunit 1 (SF3B1), a critical component in RNA splicing and processing. SF3B1 mutations strongly correlated with the presence of del(11q), ATM mutations, or both, as well as a short time to initial treatment. Investigations are under way to better understand the pathogenetic mechanisms associated with the generation of aberrant RNA transcripts.

Comment: This discovery of mutations in this key component of RNA processing parallels those previously identified in CLL regulatory microRNAs). Of note, SF3B1 mutations are also present in myelodysplastic syndromes, especially refractory anemia with ringed sideroblasts), and less commonly in solid tumors, indicating that these mutations might underlie the pathogenesis of disparate cancer types.

Source: Journal Watch Oncology and Hematology