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Combination therapy shows promise for chronic myeloid leukemia Mouse study results could lead to potential cure, significantly reduced treatment costs


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#1 CallMeLucky

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Posted 08 September 2016 - 04:43 PM

https://www.mdanders...n-therapy-.html

 

A study in mice combining two inhibitor drugs for treatment of chronic myeloid leukemia (CML) has revealed potential for not only stopping the disease completely, but also significantly lowering the cost for treatment. CML is a cancer of the white blood cells accounting for 20 percent of adult leukemia.

The study at The University of Texas MD Anderson Cancer Center was led by Michael Andreeff, M.D., professor, and Bing Carter, Ph.D., professor, both of the department of Leukemia. Findings were published in the Sept. 7 online issue ofScience Translational Medicine.

Researchers combined the BCR-ABL tyrosine kinase inhibitor (TKI), with another inhibitor drug known as venetoclax, and observed encouraging response and cure rates for both the chronic phase of the disease and its fatal end-stage phase called blast crisis. BCR-ABL inhibitors are the current standard-of-care treatment allowing most patients to remain in remission, but they do not entirely eradicate the cancer cells. In some patients, the cancer returns in a form that is untreatable. Approximately 100,000 patients in the U.S. are kept on life-long TKI therapy at a cost of $100,000 annually, a treatment that is unaffordable for many patients.

"Our results demonstrate that this study in mice employing combined blockade of BCL-2 and BCR-ABL has the potential for curing CML and significantly improving outcomes for patients with blast crisis, and, as such, warrants clinical testing," said Andreeff. "This combination strategy may also apply to other malignancies that depend on kinase signaling for progression and maintenance."

TKIs for CML are the most successful class of molecular targeted therapy of any malignant disease, but are not effective in eliminating CML stem cells. Since the persistent stem cells could allow the cancer to return and advance to the fatal blast crisis stage, patients must remain on the drugs for the rest of their lives.

"It is believed that TKIs do not eliminate residual stem cells because they are not dependent on BCR-ABL signaling," said Carter. "Hence cures of CML with TKIs are rare."

Carter has worked for several years on eliminating the residual CML stem cells, which could mean CML patients no longer would require expensive lifelong TKIs. Based on this study, combining TKIs with BCL-2 inhibitor, an agent pioneered by Andreeff's group for use in both acute and chronic myeloid leukemias, may be a solution.

"Long-term treatment with TKIs comes at a high cost, both in terms of side effects and financially," she said. "Worldwide, most CML patients cannot afford the extraordinary expenses associated with TKI-based therapy. And, unfortunately, for patients who progress to blast crisis, there are no meaningful treatments and survival is counted in weeks or months."

MD Anderson members of the study team included Po Yee Mak; Hong Mu, M.D., Ph.D.; Hongsheng Zhou, M.D.; Duncan H. Mak; Wendy Schober; Marina Konopleva, M.D., Ph.D.; Jorge Cortes, M.D.; and Hagop Kantarjian, M.D., all of Leukemia; and Xuelin Huang, Ph.D., Biostatistics. Other participating institutions included AbbVie, Inc., North Chicago, Ill.; City of Hope Cancer Center, Duarte, Calif.; and the University of Alabama at Birmingham.

The study was funded by National Institutes of Health (P01CA49639 and P30CA016672), the Paul and Mary Haas Chair in Genetics and Abbvie Inc.

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Date  -  Lab  -  Scale  -  Drug  -  Dosage MG  - PCR
2010/Jul -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 1.2%
2010/Oct -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.25%
2010/Dec -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.367%
2011/Mar -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.0081%
2011/Jun -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2011/Sep -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.00084%
2011/Dec -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Mar -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.004%
2012/Jun -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Sep -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Dec -  MSKCC  -  Non-IS  -  Sprycel  - 100 - 0%
2013/Jan -  Quest  -  IS  -  Sprycel  -  50-60-70  - 0%
2013/Mar -  Quest  -  IS  -  Sprycel  -  60-70  - 0%
2013/Apr -  CUMC  -  Non-IS  -  Sprycel  - 50 - 0.036%
2013/May -  CUMC  -  Non-IS  -  Sprycel  - 50 - 0.046%
2013/Jun -  Genoptix  -  IS  -  Sprycel  - 50 - 0.0239%
2013/Jul -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0192%
2013/Jul -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0034%
2013/Oct -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0054%
2014/Jan -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0093%
2014/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0.013%
2014/Apr -  Genoptix  -  IS  -  Sprycel  - 100 - 0.0048%
2014/Jul -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2014/Nov -  Genoptix  -  IS  -  Sprycel  - 100 - 0.047%
2014/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0.0228%
2016/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Dec - Genoptix  -  IS  -  Sprycel  -  100 - 0%
 

 


#2 gerry

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Posted 08 September 2016 - 05:00 PM

Great news for people in blast phase, but I don't get how they know it is a cure.

#3 r06ue1

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Posted 09 September 2016 - 05:54 AM

Very interesting stuff, seems to be a lot of different routes to a cure for CML coming in the next five or so years.  


08/2015 Initial PCR: 66.392%

12/2015 PCR: 1.573%

03/2016 PCR: 0.153%

06/2016 PCR: 0.070%

09/2016 PCR: 0.052%

12/2016 PCR: 0.036%

03/2017 PCR: 0.029%

06/2017 PCR: 0.028%

09/2017 PCR: 0.025%

12/2017 PCR: 0.018%

 

 

Taking Imatinib 400 mg


#4 scuba

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Posted 09 September 2016 - 08:07 AM

I noted that Dr. Cortes is on the study team. I am his patient and will follow up with him on next steps they are taking to move this to the clinic. 

 

The key drug Venetoclax is very new:

http://www.ibtimes.c...etoclax-2412087

 

It is going through clinical trials for primary application in CLL

 

https://en.wikipedia...wiki/Venetoclax

 

I told Dr. Cortes - sign me up for a combo trial when ready.


Diagnosed 11 May 2011 (100% FiSH, 155% PCR)

with b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL protein

 

Sprycel: 20 mg per day - taken at lights out with Quercetin and/or Magnesium Taurate

6-8 grams Curcumin C3 complex.

 

2015 PCR: < 0.01% (M.D. Anderson scale)

2016 PCR: < 0.01% (M.D. Anderson scale) 

March        2017 PCR:     0.01% (M.D. Anderson scale)

June          2017 PCR:     "undetected"

September 2017 PCR:     "undetected"


#5 kat73

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Posted 09 September 2016 - 11:04 AM

Right, Gerry, I don't get it either - how does this kill the CML-causing stem cells forever, without hurting regular blood-creating cells?


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 CallMeLucky

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Posted 09 September 2016 - 11:32 AM

It is a BCL-2 inhibitor, which I guess they are finding disrupts CML stem cells.  This is being trial'd for CLL and I think for AML.

 

They did the CML test using mice.  Big difference between a human and a mouse but still exciting step in the right direction.  I like that there is so much cost pressure people are still looking for a cure and not satisfied with life long treatment.


Date  -  Lab  -  Scale  -  Drug  -  Dosage MG  - PCR
2010/Jul -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 1.2%
2010/Oct -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.25%
2010/Dec -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.367%
2011/Mar -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.0081%
2011/Jun -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2011/Sep -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.00084%
2011/Dec -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Mar -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.004%
2012/Jun -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Sep -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Dec -  MSKCC  -  Non-IS  -  Sprycel  - 100 - 0%
2013/Jan -  Quest  -  IS  -  Sprycel  -  50-60-70  - 0%
2013/Mar -  Quest  -  IS  -  Sprycel  -  60-70  - 0%
2013/Apr -  CUMC  -  Non-IS  -  Sprycel  - 50 - 0.036%
2013/May -  CUMC  -  Non-IS  -  Sprycel  - 50 - 0.046%
2013/Jun -  Genoptix  -  IS  -  Sprycel  - 50 - 0.0239%
2013/Jul -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0192%
2013/Jul -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0034%
2013/Oct -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0054%
2014/Jan -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0093%
2014/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0.013%
2014/Apr -  Genoptix  -  IS  -  Sprycel  - 100 - 0.0048%
2014/Jul -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2014/Nov -  Genoptix  -  IS  -  Sprycel  - 100 - 0.047%
2014/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0.0228%
2016/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Dec - Genoptix  -  IS  -  Sprycel  -  100 - 0%
 

 


#7 scuba

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Posted 09 September 2016 - 02:08 PM

Right, Gerry, I don't get it either - how does this kill the CML-causing stem cells forever, without hurting regular blood-creating cells?

 

http://www.ncbi.nlm....les/PMC3595363/

 

http://www.ncbi.nlm....pubmed/24394664


Diagnosed 11 May 2011 (100% FiSH, 155% PCR)

with b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL protein

 

Sprycel: 20 mg per day - taken at lights out with Quercetin and/or Magnesium Taurate

6-8 grams Curcumin C3 complex.

 

2015 PCR: < 0.01% (M.D. Anderson scale)

2016 PCR: < 0.01% (M.D. Anderson scale) 

March        2017 PCR:     0.01% (M.D. Anderson scale)

June          2017 PCR:     "undetected"

September 2017 PCR:     "undetected"


#8 Trey

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Posted 09 September 2016 - 04:14 PM

This was also discussed in another thread:

http://community.lls...toclax-for-cml/



#9 gerry

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Posted 09 September 2016 - 04:49 PM

Trey,

If they can say the word "cure", how are they testing it on humans to know for sure.

We had someone relapse at 4 1/2 years TFR, so I figure testing is just part of a CMLers life, no matter what stage.



#10 kat73

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Posted 09 September 2016 - 05:25 PM

So, pursuing this BCR2 thingy looks like it's going to be a winner?  WHEN????


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.


#11 Trey

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Posted 09 September 2016 - 09:00 PM

G,

The only test for a cure is time without relapse, just like any other cancer.  But our time without relapse must be longer than the traditional 5 years, maybe as long as 15 years.  So I think there will be a lot more latent TRF relapses during cessation.  It just makes sense the way the disease works.  If the leukemic stem cells are still "in there", the CML will come back some day if the TKI drugs are stopped.  No one even knows what a high level leukemic stem cell looks like, so no one can say when they are all gone since we don't know what we are looking for.  If anyone ever captured one in a BMB they did not recognize it.  Remember, cancer is self, even though mutated.

 

K,

Like many other things which have looked like winners, the answer is "maybe, but unlikely".  Curing CML will either be a whack-a-mole approach (where we plug one hole then another then another then another then...) or it will be more elegant solution.  The TKI drugs target an Achilles heel of the leukemia at the mid-level progenitor cells.  A cure must target the very existence of the highest level leukemic stem cells.  And they are very good survivors.

 

Pathway inhibition is a W-A-M approach, and has its merits.  But if we are talking cure it must be self on self warfare.  So teaching our immune system to target leukemic cells, without targeting normal cells (autoimmune and GVHD), is the key.

 

Patience, patients.



#12 kat73

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Posted 10 September 2016 - 10:49 AM


 

 

K,

Like many other things which have looked like winners, the answer is "maybe, but unlikely".  Curing CML will either be a whack-a-mole approach (where we plug one hole then another then another then another then...) or it will be more elegant solution.  The TKI drugs target an Achilles heel of the leukemia at the mid-level progenitor cells.  A cure must target the very existence of the highest level leukemic stem cells.  And they are very good survivors.

 

Pathway inhibition is a W-A-M approach, and has its merits.  But if we are talking cure it must be self on self warfare.  So teaching our immune system to target leukemic cells, without targeting normal cells (autoimmune and GVHD), is the key.

 

Patience, patients.

 

Trey - This is, by far and word for word, the single most brilliant summing up of our challenge that I have ever read.  Many thanks.


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.


#13 r06ue1

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Posted 26 September 2016 - 06:05 AM

Scuba, did you find out anything more from your last appointment about this combination therapy?  


08/2015 Initial PCR: 66.392%

12/2015 PCR: 1.573%

03/2016 PCR: 0.153%

06/2016 PCR: 0.070%

09/2016 PCR: 0.052%

12/2016 PCR: 0.036%

03/2017 PCR: 0.029%

06/2017 PCR: 0.028%

09/2017 PCR: 0.025%

12/2017 PCR: 0.018%

 

 

Taking Imatinib 400 mg


#14 scuba

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Posted 26 September 2016 - 08:25 AM

Scuba, did you find out anything more from your last appointment about this combination therapy?  

 

Yes - it's too soon for combination trial. venetoclax is still going through safety trials although approved for CLL. Combination work with TKI's for CML is just starting (... in rats).


Diagnosed 11 May 2011 (100% FiSH, 155% PCR)

with b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL protein

 

Sprycel: 20 mg per day - taken at lights out with Quercetin and/or Magnesium Taurate

6-8 grams Curcumin C3 complex.

 

2015 PCR: < 0.01% (M.D. Anderson scale)

2016 PCR: < 0.01% (M.D. Anderson scale) 

March        2017 PCR:     0.01% (M.D. Anderson scale)

June          2017 PCR:     "undetected"

September 2017 PCR:     "undetected"





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