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Strategies to Reduce the Use of Tyrosine Kinase Inhibitors in CML


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#1 gerry

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Posted 13 April 2017 - 08:49 PM

SSan Diego, CA—Although tyrosine kinase inhibitors (TKIs) including imatinib (Gleevec), nilotinib (Tasigna), and dasatinib (Sprycel), have dramatically improved outcomes in patients with chronic myeloid leukemia (CML), the costs of these drugs have spiraled out of control, causing some patients to stop treatment or cut their dosage because of financial toxicity. Data presented at the 2016 American Society of Hematology meeting show that it is possible for some patients with CML to reduce their TKI dose by 50% and maintain remission, perhaps even stop treatment altogether once deep and durable remission has been achieved after approximately 5 years of treatment.

Experts interviewed for this article agreed that the evidence is stronger for reducing the dose of TKI therapy than for stopping treatment altogether, because approximately 50% of patients who stop taking their drugs will have disease relapse.

Dose Reduction

The National Comprehensive Cancer Network guidelines for CML suggest continuing treatment indefinitely for patients who are in remission, but this may not be necessary for all patients; the side effects of TKIs can be difficult to tolerate and the cost of treatment is high.

In the British De-escalation and Stopping Therapy with Imatinib, Nilotinib, or Sprycel (DESTINY) study, investigators explored the effects of reducing the standard dose of TKI by 50% in 174 patients with a molecular response (MR) of MR4 (ie, undetectable disease or better), as well as MR3 (less-deep responses).

"As patients proceeded through de-escalation of therapy, we saw significant reductions in many side effects within the first 3 months of reduced dose therapy. After that, there was no further improvement in symptoms over time," said study co-investigator Mhairi Copland, MBChB, PhD, FRCP, FRCPath, Institute of Cancer Sciences, University of Glasgow, United Kingdom.

Overall, 93% of patients showed no evidence of disease recurrence within 12 months of TKI dose de-escalation. Patients with molecular relapses (N = 12) were documented by month 12 of TKI dose de-escalation. The relapse rate was 18.4% in patients with MR3 at baseline (N = 49), and 2.4% in patients with MR4 at baseline (N = 125). The median time to relapse was 4.4 months in the sustained MR3 group versus 8.7 months in the sustained MR4 group.

When patients whose disease relapsed received TKI re-treatment at full doses, they attained MR3 by 4 months.

The dose de-escalation of TKI therapy reduced the costs of treatment by 46.7%. A 50% reduction in TKI saved £1,943,364 from an expected TKI cost of £4,156,969. The costs were reduced by 47% in the MR4 group and by 44.2% in the MR3 group.

TKI Withdrawal

Interim results of the EURO-SKI clinical trial showed that approximately 50% of 755 patients with CML who stopped TKI therapy had disease relapse by 15 months, and 78.3% had disease relapse within 6 months of stopping TKI therapy. These patients received TKIs for at least 3 years and had deep molecular remission (MR4) for at least 1 year before entering the study.

At 12 months, molecular recurrence-free survival was 55%; at 24 months, it was 50%; and at 36 months, it was 47%.

"Several studies have shown the feasibility of stopping TKI treatment, with consistent results over time. A sustained deep molecular remission over long-term TKI therapy seems to be necessary to attempt stopping therapy," said lead investigator Francois-Xavier Mahon, MD, PhD, University of Bordeaux, France. "With decentralized but standardized PCR [polymerase chain reaction] monitoring, stopping TKI therapy in a large cohort of patients with CML appears feasible and safe."

"Longer duration of imatinib therapy, optimally more than 5 years, prior to stopping therapy, correlates with a higher probability of relapse-free survival. Sex, age, and Sokal scores do not predict the probability of successfully stopping TKI," he added.

Mikkael A. Sekeres, MD, MS, Director, Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, OH, who was not involved in this study, said that he was more reassured by the dose de-escalation study than by the EURO-SKI study results.

"If I see more data reassuring me that the depth of remission is the same when relapsed patients [who stop their TKI] are restarted on therapy, then I will rethink the strategy of stopping TKI," he said.



#2 gerry

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Posted 13 April 2017 - 08:57 PM

Reducing the Dose of Leukemia Drug Can Minimize Side Effects of the Therapy

 

Highlights

  • Chronic Myeloid Leukemia is characterized by cancer that starts in certain blood-forming cells of the bone marrow.
  • Tyrosine kinase Inhibitor drugs can improve treatment options for leukemia, but its use is questioned due to side effects and treatment cost.
  • Halving the dose of the drug can reduce side effects of the therapy.
Side effects of life-long treatment of leukemia drug can be cut down by reducing the dose into half, finds a new study from the University of Liverpool.
Chronic Myeloid leukemia is a type of cancer that occurs in the blood-forming cells of the bone marrow. Acute or chronic state of leukemia depends on whether the abnormal cancer cells are either mature or immature.
The study findings were presented at the American Society of Hematology Annual Meeting held at San diego, California.

Tyrosine- kinase inhibitors are found to improve leukemia treatment through a daily pill. Drugs like imatinib, bosutinib are found to be useful options for leukemia treatment.
Leukemia drugs are highly effective. However, the treatment cost and side effects of the drugs have led several questions to doctors and patients on whether to continue the medications or not.
Current guidelines state that tyrosine kinase inhibitor therapy should be continued by patients. Side effects of the therapy may include stomach problems, chronic headaches and fatigue. Drugs taken during pregnancy may also lead to birth defects.
A new research study from the University of Liverpool has found that reducing the dose of the drug to half can help to minimize side effects of the therapy.
The research study conducted on 174 participants shows 93% of no evidence on leukemia relapse for one year after halving the dose. These patients also reported a decrease in the side effects within the three months.
Only 12 participants showed signs of leukemia relapse after resuming full dose of the drug within four months. And patients with low levels of leukemia are less likely to suffer from relapse when compared to those who are at a severe stage (MR3 remission).
Richard Clark, University's Institute of Translational Medicine, said "Low rates of rebound overall suggest it is safe for MR3 patients to reduce their TKI dose if desired. Any benefits in terms of reducing side effects should become apparent within the first three months."
"Taken together, these findings indicate that some patients are being unnecessarily over-treated.
"The other important implication is that patients do not have to have extremely low levels of leukaemia on very sensitive tests in order to safely try reducing their TKI dose." he added.

 

http://www.medindia....y-165950-1.htm 



#3 kat73

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Posted 14 April 2017 - 10:02 AM

Thanks for these, Gerry.  I'm still sort of stunned that I lost two logs in two months, stopping Sprycel for a pleural effusion.  I'm back on 50 mg, so it'll be interesting to see how long it takes to get back to <0.01.


Dx July 2009 on routine physical.  WBC 94.  Started Gleevec 400 mg Sept 2009.  MMR at 2yrs.  Side effects (malaise, depression/anxiety, fatigue, nausea, periorbital edema) never improved.  Kidney issues developed because of Gleevec.  Switched to Sprycel 70 mg in Aug 2011.  Above side effects disappeared or improved.  Have been MR3.5 - 4.5 ever since.  Two untreated pleural effusions followed by one treated by stopping Sprycel Jan 2017.  After 9 weeks, PCR showed loss of MMR; re-started Sprycel at 50 mg and in 3 months was back to <0.01% IS.  Pleural effusion returned within a couple of months, same as before (moderate, left side only).  Stopped Sprycel 50 mg for 12 weeks; pleural effusion resolved.  At about a monthoff the drug, PCR was 0.03; at 11 weeks it was 2.06 - lost CCyR? Have returned to 50 mg Sprycel for 3 weeks, intending to reduce to 20 mg going forward.


#4 gerry

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Posted 14 April 2017 - 01:51 PM

It is freight train speed apparently if it is coming back. But you are also looking at figures that are after the decimal point. I have a friend that had a go at stopping prior to me, she was only on 200mg Gleevec and restarted on that and returned to negative. Sprycel is stronger so you should be back to where you were sooner or later. :-)

#5 kat73

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Posted 14 April 2017 - 04:35 PM

Hope so, thanks, Gerry.


Dx July 2009 on routine physical.  WBC 94.  Started Gleevec 400 mg Sept 2009.  MMR at 2yrs.  Side effects (malaise, depression/anxiety, fatigue, nausea, periorbital edema) never improved.  Kidney issues developed because of Gleevec.  Switched to Sprycel 70 mg in Aug 2011.  Above side effects disappeared or improved.  Have been MR3.5 - 4.5 ever since.  Two untreated pleural effusions followed by one treated by stopping Sprycel Jan 2017.  After 9 weeks, PCR showed loss of MMR; re-started Sprycel at 50 mg and in 3 months was back to <0.01% IS.  Pleural effusion returned within a couple of months, same as before (moderate, left side only).  Stopped Sprycel 50 mg for 12 weeks; pleural effusion resolved.  At about a monthoff the drug, PCR was 0.03; at 11 weeks it was 2.06 - lost CCyR? Have returned to 50 mg Sprycel for 3 weeks, intending to reduce to 20 mg going forward.


#6 PhilB

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Posted 28 April 2017 - 04:29 AM

The good news is that with Imatinib now out of patent, the drug companies can't respond to people halving their dosage by doubling the price!



#7 hannibellemo

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Posted 28 April 2017 - 07:41 AM

Oh geez, PhilB, I never thought of that!


Pat

 

"You can't change the direction of the wind but you can adjust your sails."

DX 12/08; Gleevec 400mg; liver toxicity; Sprycel 100mg.; CCyR 4/10; MMR 8/10; Pleural Effusion 2/12; Sprycel 50mg. Maintaining MMR; 2/15 PCRU; 8/16 drifting in and out of undetected like a wave meeting the shore. Retired 12/23/2016! 18 months of PCRU, most recent at Mayo on 7/25/17 was negative at their new sensitivity reporting of 0.003.<p>


#8 PhilB

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Posted 28 April 2017 - 08:59 AM

For monopoly drugs the marginal cost of production is peanuts compared to the sales price - which is all about 'how much can we get away with per patient'.  If dosages halve generally, then you can bet the only results will be a doubling of price and a small increase in profits for the drug company.  Thankfully patents have expiry dates, despite the best efforts of the companies to evergreen them.






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