I have tried to put together some information to help CML patients understand the second-line CML drugs, Sprycel (dasatinib) and Tasigna (nilotinib), so they can have a more informed discussion with their Onc when a drug change is being considered. When Gleevec fails or a patient becomes intolerant of it, the best second-line drug is the one that will most effectively control the CML and also provide an acceptable level of side effects. These two issues can be different for each person. So choosing the better second-line drug should be a thoughtful process, not merely a random selection.
Gleevec is currently the only drug approved to be used as the initial tyrosine kinase inhibiter (TKI) drug for treatment of CML. Sprycel or Tasigna are only allowed to be prescribed if Gleevec quits working (resistance), does not provide good results (suboptimal performance), or the side effects are unbearable. However, there is a considerable degree of latitude given to Oncs in determining that a switch is needed. Clinical trials are underway testing Sprycel and Tasigna as potential first-line drugs. More drugs are also being developed, which will make it tougher to choose a second-line drug, but that is good news. So the “problem” of choosing a second-line drug is a good problem to have.
Both Gleevec and Tasigna are Novartis drugs, and Sprycel is a Bristol-Meyers-Squibb drug. Tasigna is generally viewed as a stronger form of Gleevec that works in a similar way as Gleevec, but binds to the BCR-ABL more tightly than Gleevec (in overly simplified terms). So it can be thought of as a stronger form of Gleevec. Sprycel binds to the BCR-ABL differently than Gleevec or Tasigna, and binds in a different BCR-ABL location, which is why it does not violate the Gleevec patent. (If Tasigna was not a Novartis drug, it would violate the Gleevec patent since it is so similar in function.) But overall, both Sprycel and Tasigna are very effective drugs. Tasigna costs more than Sprycel, and both cost more than Gleevec at the lowest dosages. Tasigna is approved for Chronic and Accelerated CML phases, but not Blast phase. Sprycel is approved for all 3 phases. Tasigna has a bloodstream half-life of about 17 hours while Sprycel is only about 5 hours.
Technically speaking, Gleevec and Tasigna only shut down the inactive form of the leukemic gene BCR-ABL (i.e., when the gene is turned off). But Sprycel shuts down BCR-ABL in both active and inactive configurations, which has advantages. Gleevec and Tasigna inhibit BCR-ABL, cKit, & PDGR. Sprycel inhibits all those and also inhibits SRC. The additional SRC inhibition enables Sprycel to fight CML in some unique ways, but also causes a new form of side effects (such as the pleural effusion).
There is no right or wrong decision in choosing between these two drugs when Gleevec fails or one becomes intolerate due to side effects. But my theory is that if Gleevec is not working, why not switch to the drug which is most unlike Gleevec. Sprycel inhibits all the things that Gleevec and Tasigna inhibit, but also inhibits an enzyme/pathway in the cell called SRC which neither Gleevec nor Tasigna inhibit. Sometimes the leukemia can do an end-run around the BCR-ABL process and use the SRC pathway as a back door to survive and regain control. If you inhibit both BCR-ABL and SRC pathways, then you will more likely shut down the leukemic cells. Also, Sprycel can kill off some intermediate level leukemic stem cells better than either Gleevec or Tasigna. That is why I say that I would personally switch to Sprycel if forced to switch from Gleevec some day. But you can also use the "flip the coin" method of chosing between Sprycel and Tasigna. They are both very good drugs. But remember that if there is a kinase mutation causing the Gleevec failure, then the drug choice should be made more carefully.
Oncs like to think in terms of progression of drug use based generally on what other Oncs have done (precedence). In the case of the TKI drugs, the theory seems to be that Gleevec was approved by the FDA first, then Sprycel, then Tasigna, so they often merely prescribe them in that order. Another issue is that Sprycel is “more different” from Gleevec than Tasigna, so it may be viewed by some Oncs as a more significant change. So a generally accepted theory of “Gleevec first, then Sprycel, then Tasigna” has developed, but not based on hard science. A business journal that covers the pharmaceutical industry says: “Sprycel currently commands a higher market share than Tasigna for CML, benefiting from its first-to-market advantage. However, physicians' perceptions of Sprycel and Tasigna show little differentiation, and there will be close competition for market share in the coming years.”
In general, both Sprycel and Tasigna are effective after Gleevec failure, but each has its own strengths and weaknesses. The data on both drugs continues to be very encouraging for those who fail Gleevec, even when most mutations occur, with the notable exception of T315i.Recent papers cited below provide updates on large groups of CML patients who failed Gleevec, and how they have responded to both Sprycel and Tasigna.
The following paper provides a 2 year update on Sprycel (Dasatinib) effectiveness from the START-C group (387 CML patients) for those who failed Gleevec for intolerance or resistance (including mutations):
http://journals.lww.com/oncology-times/Fulltext/2008/02101/Dasatinib_Responses_Durable_in_Chronic_Phase_CML.16.aspx
The following paper provides an update on Tasigna (Nilotinib) effectiveness from a group of 321 CML patients for those who failed Gleevec for intolerance or resistance (including mutations).
http://www.cancernetwork.com/display/article/10165/1161471
Good overall paper on the issue:
http://www.cmlsupport.org.uk/?q=system/files/Mechanisms+of+Resistance+-+Imatinib.pdf
ASH 2009 paper on 2nd Generation TKI response:
http://ash.confex.com/ash/2009/webprogram/Paper22236.html
As I view it, there are several important issues to consider when selecting between Sprycel and Tasigna, depending on the cause of the Gleevec switch:
1) The most important issue to consider when switching drugs pertains to Gleevec resistance caused by a kinase mutation. This is why a kinase mutation test is important when Gleevec fails. If the drug switch is required because of resistance caused by an acquired kinase mutation, then the selection must be made carefully since Sprycel works better for some mutations, and Tasigna works better against others, and neither work against T315i. So the answer is not automatically one or the other. Here is a mutation effectiveness comparison chart for the two drugs:
http://www.cmlsupport.org.uk/?q=system/files/2007_O%C2%B4Hare_Blood_BCR-ABL+KD+Mutations_TKIs_0.pdf
(See Figure 1 in above link)
http://bloodjournal.hematologylibrary.org/cgi/content/full/114/10/2037#T5
http://www.jci.org/articles/view/30890
2) If the switch is needed due to Gleevec failure NOT related to a kinase mutation (so usually unknown cause), then the selection of the follow-on drug is often based on other issues, such as side effects profile. Otherwise the drugs can often be considered to be roughly equally effective. So the selection process might focus more on side effects. However, since Sprycel inhibits the SRC kinases (unlike Tasigna or Gleevec), Sprycel can work better as a second line drug if Gleevec failure is related to SRC issues (such as LYN over-expression, which will not be known).
3) If the switch is required because of some form of intolerance due to severe side effects, then the side effects issue becomes the foremost consideration. Each person has a unique set of side effects.
For #2 and 3 above, here is a good head-to-head comparison of Gleevec, Sprycel & Tasigna and does a very good job comparing the side effects of each:
http://www.hemonctoday.com/article.aspx?rid=30195
In general, the above link shows that Sprycel does not cause the muscle cramping or rash problems that Gleevec has as side effects. But Sprycel can be harder on the liver, can cause lower phosphate levels (necessary for electrolyte balance and good bone health), and has worse fluid retention issues (including possible fluid build-up in the lungs) compared to Gleevec. Gleevec can cause worse bone and muscle pain than the others. Tasigna seems to have the lowest overall side effects unless a person has some specific heart related issues (prolonged QT interval), although larger studies seem to show the QT interval issue is not as significant as once believed. Of course, side effects can vary from person to person.
Sprycel Specific Info:
Here are a couple detailed data sheets on Sprycel, for those taking it. They provide a lot of information about the drug:
http://www.medsafe.govt.nz/consumers/cmi/s/sprycel.htm
http://www.emea.europa.eu/humandocs/PDFs/EPAR/sprycel/H-709-en6.pdf
Here is some information about Sprycel for those with sub-optimal responses to Gleevec:
Here are some useful links on Sprycel:
http://www.rxlist.com/cgi/generic/sprycel_ad.htm
http://www.drugs.com/sprycel.html
Here is a support group forum called "Sprycel Talk":
http://www.newcmldrug.com/bms_discuss/default.asp
For those on Sprycel, here is the result of a study of pleural effusion (fluid build-up in the lung region) that included 138 Sprycel patients:
Summary: Pleural effusion occurred in 48 of 138 Sprycel patients (35%); 17% of those were grade 3 or 4. It is more likely to occur in accelerated phase and blast phase. Management included temporary interruption, diuretics, pulse steroids, and thoracentesis (using a needle to draw out fluid). A twice-daily dosage schedule may result in a higher incidence of pleural effusion.
Here is some info about the Sprycel drug reimbursement program:
http://www.destinationaccess.com/index.aspx?bmscontentpg=sprycel
Tasigna Specific Info:
Here is some overview info on Tasigna:
http://www.medicalnewstoday.com/articles/155782.php
http://www.medsafe.govt.nz/profs/Datasheet/t/Tasignacap.htm
Here is a good comparison of Tasigna to Gleevec. Essentially it shows that Tasigna works faster and better than Gleevec:
Tasigna side effects are listed at this website, but there are usually others that pop up.
http://www.drugs.com/tasigna.html
Here are links to some detailed data on Tasigna, for those taking it. They provide a lot of information about the drug:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf
http://www.medsafe.govt.nz/profs/Datasheet/t/Tasignacap.htm
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/notices-avis/conditions/tasigna_fs_fd_110305-eng.php
The drug interaction checker says for both those drugs "generally avoid" combining these with Tasigna. The rationale is as follows:
"Theoretically, coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction."
http://www.drugs.com/drug_interactions.php
Here is a group that discusses Tasigna, and you might want to post a question there also:
http://www.newcmldrug.com/amn_Discuss/default.asp
Here is some info about the Tasigna drug assistance program:
Pleural Effusion related to both Sprycel and Tasigna:
