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Glivec FAQ

Targeting Bcr-Abl in Ph+ CML

The World Health Organization classifies CML as a myeloproliferative disease characterized by the presence of the Ph+ chromosome or the BCR-ABL fusion oncogene.

To see a video of the BCR-ABL role in Ph+ CML, click here.

The hallmark of CML, the Ph+ chromosome, produces the constitutive activation of the Bcr-Abl tyrosine kinase, an abnormal protein within the leukemic cell. It has been shown that Bcr-Abl is the single, definitive cause of Ph+ CML and remains the key cause of the disease throughout the chronic phase (CP). Therefore, maintaining effective suppression of Bcr-Abl can reduce the risk of progression to advanced stages of disease, where Bcr-Abl–independent mechanisms may begin to play a role.

Work began in early 1990 on the discovery of Bcr-Abl tyrosine kinase inhibitors (TKIs) by researchers. Imatinib (Glivec) was the first TKI to reach the clinic. By targeting Bcr-Abl, the specific causue of Ph+ CML, imatinib produced significant improvements in efficacy and tolerability for patients with Ph+ CML.

Since Ph+ CML-CP is a single-target disease, it was determined that multitargeted agents were unlikely to provide additional benefit in this setting, and a growing body of evidence suggested that they may produce unnecessary off-target adverse effects when compared with agents that target Bcr-Abl.

Imatinib (Glivec) quickly became the new standard of care in Ph+ CML. 
 
 
 
How does Glivec work?
Glivec is a unique therapy that specifically targets the root cause of CML. As mentioned earlier, there are constant signals in patients with CML that tell the body to keep producing abnormal white blood cells. Glivec works by blocking, or turning off, the signals so that the extra white blood cells are not made. This is the first time a therapy has targeted the cause of CML. Glivec specifically targets the signal that produces leukaemic cells, so most healthy cells are left unharmed. Most patients receiving Glivec do not have serious problems with side-effects.
What to expect from Glivec therapy.
Is is important to remember that people respond differently to therapy. How you respond to treatment with glivec will depend on many factors, but your doctor has prescribed glivec for you because he or she believes that you might benefit from it. There are two main treatment goals with glivec therapy. The first is to decrease the number of abnormal white blood cells in your circulation. The second goal is to prevent your disease from getting worse, or even reverse it to a less serious stage. It is possible that your therapy with glivec will accomplish both of these goals. Your doctor will regularly monitor your condition to determine whether Glivec is having the desired effect. Your weight and blood will also be tested regularly while you are receiving this treatment.
What possible side-effects can occur?
As Glivec is designed to specifically target leukaemic cells, most normal cells are left unharmed. Patients receiving Glivec therapy do not typically have serious problem with side-effects. The most common side-effects are mild nausea, vomiting, diarrhoea, muscle pain and muscle cramps - and are manageable. Swelling around the eyes or lower legs is also common. However, a small number of patients have more serious side-effects, which may make it necessary to interrupt or discontinue therapy. The most common side-effects seen with Glivec therapy can be managed as shown below. If you experience any worsening side-effects during Glivec therapy, or other side-effects not listed here, contact your doctor. nausea The most common side-effects with Glivec is mild nausea, sometimes accompanied by vomiting or upper abdominal pain. Taking Glivec with a large meal and a large glass of water will greatly reduce these effects. diarrhoea Some patients have also had diarrhoea while receiving Glivec. If you experience diarrhoea during Glivec therapy, contact your doctor before taking any other drugs. Diarrhoea is usually mild. muscle pain Some patients have muscle pain or muscle cramps while taking Glivec. Contact your doctor if you experience this side-effect. water retension Water retension and weight gain have been reported by patients taking Glivec. If you notice any increase in weight, or swelling around the eyes, lower legs or other areas while taking glivec, notify you doctor. You may be given a drug called a diuretic, which makes you pass urine, to reduce the amount of water in your body. rash Some patients taking Glivec develop a skin rash. If you notice any red patches or itchiness, contact your doctor. You may be given an additional medicine to reduce the signs and symptoms of rash. If additional treatment does not help and the rash grows severe, your doctor may find it necessary to interrupt or even discontinue your therapy. infection Treatment with Glivec may decrease the number of white cells in your blood, which can lead to a higher sensitivity to infection. Consult your doctor immediately if you experience signs of infection such as fever, severe chills, sore throat, or mouth ulcers. You should also inform your doctor immediately if your skin appears yellowish in tone. If you experience worsening of any of the side-effects listed above, or any side-effects not mentioned in this leaflet, contact your doctor.
Taking Glivec with other drugs?
Like many therapies, Glivec can affect, and can be affected by, other pharmaceutical products you may be taking. Talk to your doctor if you are taking other medications. Whilst taking Glivec, you should avoid taking over-the-counter medicines containing paracetamol and you should consult a doctor about all medicines and natural remedies you are currently taking or may take in the future. Do not drink Grapefruit juice or take St.John's Wort if you take Glivec.
Who should take special care with Glivec?
If you are allergic to any of the ingredients of Glivec listed here you should not take Glivec. The active substance of Glivec is imatinib myesolate. It is supplied in film-coated hard tablets. Each tablet contains 100mg of imatinib. The other ingredients are microcrystalline cellulose, crospovidone, magnesium stearate, and anhydrous colloidal silica. Ask your doctor if you have any further questions. Take special care with Glivec if you have or have ever had a liver problem or if you are or think you may be pregnant. Your doctor will discuss with you the potential risks of taking Glivec during pregnancy. Women of childbearing potential are advised to use effective contraception during treatment. You should not breastfeed during treatment with Glivec.
How to take Glivec?
Glivec is convenient to take. Unlike other drugs that must be administered in the hospital, Glivec is available in tablet form and is taken by mouth once a day. It is recommended that patients take Glivec with a large meal and a large glass of water to avoid nausea and digestive upset. Swallow the tablets whole, without crushing them. Some patients have found that splitting the dose and taking one half in the morning and the other in the evening has helped overcome certain side effects such as diarrhoea and/or nausea. Your doctor will advise you of the dose that you should be taking and how you should take it. Please ensure that you only take the number of capsules per day prescribed by your doctor. Glivec is supplied as 400mg and 100mg tablets. If you are in the chronic phase of CML, you will usually need to take one 400mg tablet a day. If your dose is 600mg you will usually need to take three tablets (1x400mg plus 2x100mg) per day. For those on 800mg you will need to take two x 400mg tablets a day. Depending on your response to treatment, your doctor may decide to either increase or decrease the dose of Glivec that you are taking. He or she will talk to you about the reasons for any changes to your dose. If your daily dose is changed, be sure to follow your doctor's recommendations. Because Glivec is an oral therapy, you have the important responsibility of ensuring that you take the correct dose every day. It is possible that because of occasional side-effects you will feel like taking less of your medicine, or not taking it at all. However, it is very important that you continue taking Glivec unless your doctor tells you to stop treatment. Following your prescribed dose is crucial to achieve optimal results. If you feel discouraged, talk to your doctor, a nurse, a friend or family member about the way that you feel. Emotional support during treatment is just as important as medical support.
What do the tablets look like?
The 400mg tablets are oval in shape and orange in colour. The 100mg tablets are round, scored and orange. The 400mg tablets are marked with the letters NVR SL The 100mg tablets are marked with the letters NVR SA
How are the tablets presented?
The 400mg tablets will be presented in boxes of 30 tablets, contained in three blister strips of 10 tablets each. The 100mg tablets will be presented in boxes of 60 tablets contained in 6 blister strips of 10 tablets each.
Is the tablet form as effective and well tolerated as the original capsule form?
Yes, the tablet form is as effective as the original capsule form. A study assessing the effectiveness of the two forms found that the new tablet is as effective as the original hard gelatine capsule. The researchers concluded that the tablet provides the full therapeutic effect of the capsules, but offers greater dosing convenience.>
Why is Novartis Oncology not marketing a 600mg tablet for patients on that dose?
The majority of Glivec patients are on the 400mg dose, so Novartis Oncology felt there was a substantial need for a 400mg tablet. For patients on more (or in some cases less) than 400mg/day, Novartis Oncology created a scored 100mg tablet for greater dosing flexibility. The 100mg tablet was introduced in September 2004.
If a patient is taking the 400mg tablet and develops adverse reactions, how do they manage their dosage?
All severe events must be discussed with the patient́°½€™s clinician, who will advise appropriate dosing accordingly.
Can you crush or split the tablets?
The tablets have a film-coated, which will be breached if cut or crushed, however, it is acceptable for patients to do this if required. For patients unable to swallow the tablets, it is also possible to disperse the tablets in a glass of water or apple juice. Patients should discuss the most appropriate means of administration with their clinician.
Why is the 100mg tablet scored?
The 100mg tablet is scored for dosing in paediatric patients as dosing in children is based on body size.
How to store Glivec?
# Keep glivec out of the reach and sight of children. # Do not store glivec above 30 degrees celsius. # Store glivec in its original package. # Do not use glivec after the expiry date shown on the box. # Do not use any glivec pack that is damaged or shows signs of tampering.

Ph+ CML Response Goals

Ph+ CML response goals—CHR, CCyR, and MMR


Ph+ CML typically progresses through three disease phases—chronic, accelerated, and blast crisis—characterized by worsening clinical features and laboratory findings (See Table 1).

Table 1:

CML Laboratory Parameters by Phase of Disease

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A hematological response (HR) includes reducing white blood counts to normal values, eliminating immature myeloid cells from the peripheral blood, and eradicating the signs and symptoms of disease (See Table 2 below).

Cytogenetic response is based on analysis of bone-marrow aspirates and the reduction or elimination of Ph+ cells. A complete cytogenetic response (CCyR) is defined by the absence of detectable Ph+ cells in bone marrow, and a partial cytogenetic response (PCyR) is defined as the presence of 1% to 35% Ph+ cells by standard cytogenetic techniques. Together, complete and partial responses constitute a major cytogenetic response (MCyR).1

Major molecular response (MMR) has been defined as at least a 3-log (1,000-fold) reduction below a standardized baseline derived from a median ratio of BCR-ABL to BCR obtained from 30 untreated patients with chronic-phase CML who participated in the International Randomized study of Interferon and STI571 (IRIS) trial.2

Table 2: Response measurement criteria3

 

References

  1. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.N Engl J Med. 2002;346(9):645-652.
  2. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408-2417.
  3. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041-6051.

 

Treatment Goals in Ph+CML

Today’s European LeukemiaNet (ELN) recommendations identify major molecular response (MMR) as an important component of achieving an optimal response in Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML).1 In addition, ELN recommendations support molecular monitoring as a routine standard of care for patients with Ph+ CML, as a way to measure minimal levels of residual disease.1

Residual disease can leave patients vulnerable to disease progression

Clinical evidence demonstrates that even with complete cytogenetic response (CCyR) at 12 months, residual disease can increase the incidence of disease progression.2,3 In 1 trial, significantly more patients with CCyR at 12 months had disease progression compared with patients who achieved both MMR and CCyR at 12 months.2 In a long-term follow-up of the IRIS trial, nearly 1 in 5 patients who achieved a CCyR lost their response, and 1 out of 33 patients with CCyR progressed to accelerated phase or blast crisis (AP/BC).3

MMR is a better indicator of long-term prognosis

Recent results from the ENESTnd trial, the first and largest head-to-head study designed to compare nilotinib with imatinib using MMR as the primary end point, demonstrated that the rates of MMR for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice the rate of imatinib (22%) (P<0.001 for both comparisons).4 Moreover, the study showed that no patient who had an MMR progressed to AP/BC.4

Long-term follow up from the IRIS trial also demonstrates that patients achieving an MMR had improved long-term outcomes.3 For example, patients who achieved an MMR at 12 months had a 100% rate of progression-free survival.3 This is one reason why MMR has become the new optimal goal in the treatment of Ph+ CML. By selectively targeting Bcr-Abl to reduce residual disease and achieve MMR, it is now possible to prevent progression to AP/BC phase.

 

ELN Recommendations

Leading guidelines now recommend molecular monitoring as a standard of care for patients with Ph+ CML.1,2

Both the ELN and the National Comprehensive Cancer Network (NCCN) recommend molecular monitoring every 3 months.1,2 Table 1 below identifies the new optimal treatment goals as recommended by the ELN.

 

 

References

  1. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041-6051.
  2. The NCCN Chronic Myelogenous Leukemia Clinical Practice Guidelines in Oncology (Version 2.2011). ©2010 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed November 2, 2010. To view the most recent and complete version of the guidelines, go online to www.nccn.org.

 

RQ-PCR Testing and Standardized Programs

Molecular monitoring is clearly an important and sensitive tool for evaluating responses as well as for predicting progression-free survival or relapse during targeted therapy for Ph+ CML. Although peripheral blood sampling is relatively easy to perform, obtaining reliable molecular monitoring data can be a challenge for clinicians not associated with institutions routinely performing these assays.

Lack of access to or unreliable molecular response data can compromise therapy for patients with Ph+ CML. Reliable and timely molecular monitoring during therapy has the potential to guide clinical decision making toward optimizing targeted therapy for Ph+ CML.

In a 2008 article that appeared in the journal Blood, Branford et al articulated the need for developing an international standard for comparing Bcr-Abl mRNA levels for the common interpretation of data provided by individual laboratories.1 The authors performed an alignment of Bcr-Abl values from which they were able to calculate the conversion factors used to make standardized interpretation possible.1 The results demonstrate that consistent interpretation of individual patient responses and response rates between clinical trials is possible (see Figures 1 and 2 below).1

Figure 1: Response differences before conversion


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Figure 2: Response differences after conversion

 


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Recognizing the importance of standardizing RQ-PCR testing, a network of standardized laboratories is currently emerging (see Table 1 below).2 Including local centers, there are 58 standardized labs, 26 of which are equipped to act as national reference centers for their respective countries.

With continued expansion, standardization should reach more than 200 labs across Europe in the near future. Exchange programs are well under way to educate laboratory personnel on standardized RQ-PCR testing, which will help to rapidly implement the standards in all participating European countries.

Table 1:


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Next: Guidelines and Recommendations for Monitoring CML

Note: Before prescribing, please read full European Summary of 
Product Characteristics.

References

  1. Branford S, Fletcher L, Cross NCP, et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood. 2008;112(8):3330-3338.
  2. Müller MC, Cross NCP, Erben P, et al. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia. 2009;23:1957-1963.