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Deciding factors for CML treatment


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#1 scuba

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Posted 22 December 2017 - 05:34 PM

http://www.targetedo...r-cml-treatment

 

Case: A Younger Patient With Relapsed CML

May 2013

  • A 48-year-old female was diagnosed with CP-CML with a splenomegaly, 3.2 cm below the costal margin
  • Laboratory values:
    • WBCs, 157,000/μL
    • HCT, 30% hematocrit
    • Platelets, 359,000/μL
    • Myeloblasts, 6%
  • Bone marrow biopsy: Ph+ in 20/20 metaphases
  • Q-PCR, showed a BCR-ABL1/ABL1 ratio of 176%
  • The patient was started on dasatinib 100 mg; she achieved MMR after 6 months, and a deeper molecular remission (>MR4) after 12 months on therapy and remained in remission for 3 years

December 2016

  • The patient complained of increasing fatigue and weight loss.
  • Q-PCR showed a significant increase in BCR-ABL1 transcript ratio (to 50% IS)
  • Bone marrow biopsy; 80% cellularity, 18/20 Ph+ metaphases
  • Mutation testing showed the presence of T315I
  • CBC WNL
  • The patient was started on ponatinib 45 mg daily
  • She developed grade 3 thrombocytopenia; the ponatinib dose was reduced to 30 mg daily

March 2017

  • Cytogenetics, 3/20 Ph+ metaphases
  • BCR-ABL1 transcript ratio, 5%

June 2017

  • BCR-ABL1 transcript ratio, 0.75%.

October 2017

  • BCR-ABL1 transcript ratio, 0.01% and no T315I mutation was detected

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"


#2 r06ue1

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Posted 26 December 2017 - 07:46 AM

Interesting, now would the patient be able to switch back to dasatinib since no mutation is detected?  What is the likelihood that the mutation comes from a stem cell versus a regular leukemic cell line which mutated and has since been eradicated and how many negative tests for the mutation before switching back to the original medication would be warranted?  

 

Sadly, if the mutation occurs beyond the stem cell in most patients, my guess is the doctors just keep them on the new medication which is (in this case), far more dangerous to the patient.  I wonder how many doctors actually acknowledge this and change the medication back for the patient after the mutation is no longer detectable?


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


#3 Trey

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Posted 26 December 2017 - 10:17 AM

Kinase mutations cannot be monitored when the patient is below CCyR (roughly).  So she still has T315i.



#4 r06ue1

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Posted 26 December 2017 - 11:39 AM

Understood, but do you believe that the mutation is formed in the stem cell or from the offspring and if offspring are eradicated, couldn't the patient return to the previous TKI?  

 

I suppose it would pretty difficult to find out with current technology, my point is that the patient is at risk either way (staying on the current TKI which is more harmful or taking a chance and going back to the other).


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


#5 Trey

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Posted 28 December 2017 - 05:23 PM

The kinase mutations probably start rather high.  The longest term CML stem cell(s) may not be the source, but the ones just below it likely live for a decade or longer.  But there is little known about the highest levels, including where CML begins.  There is some conjecture CML even starts above the blood making cell level, in the cells which made the blood stem cells.  Or possibly a lower level stem cell started the CML and then gained a higher order stem cell status, which sounds odd but is possible.  But the only thing that is known is that CML starts higher in the cell hierarchy than any other leukemia. 



#6 mdszj

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Posted 30 December 2017 - 06:48 AM

The kinase mutations probably start rather high.  The longest term CML stem cell(s) may not be the source, but the ones just below it likely live for a decade or longer.  But there is little known about the highest levels, including where CML begins.  There is some conjecture CML even starts above the blood making cell level, in the cells which made the blood stem cells.  Or possibly a lower level stem cell started the CML and then gained a higher order stem cell status, which sounds odd but is possible.  But the only thing that is known is that CML starts higher in the cell hierarchy than any other leukemia. 

Does this mean that cml would be the most difficult to actually cure (as opposed to turning it into a manageable chronic condition, which is what I believe the tki's do)?  Or does that not really factor into it?


dx cml 7/2012; 100 mg sprycel; splenectomy 9/2012; reached prcu 10/2013; dx smoldering myeloma 1/2015; 80 mg sprycel 12/2015; 50 mg sprycel 7/13/16; discontinued sprycel 11/15/16


#7 Trey

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Posted 30 December 2017 - 11:14 AM

Does this mean that cml would be the most difficult to actually cure (as opposed to turning it into a manageable chronic condition, which is what I believe the tki's do)?  Or does that not really factor into it?

 

That is exactly what it means, and why we know it starts so high in the stem cell hierarchy.  The higher the CML starts in the stem cell hierarchy, the more it can survive anything.  It is the hardest to kill off prior to transplant, unlike ALL, CLL, and many forms of AML.  That is one reason I do not believe TKI cessation means a complete elimination of CML stem cells, but rather that the immune system has learned to control the cells at the progenitor level.






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