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"Emerging Toxicities" and Long-Term TKI Treatment

TKI Side Effects Toxicity

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#1 LivingWellWithCML

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Posted 19 December 2014 - 07:20 AM

Hi everyone,

 

I watched Dr. Mauro's brief interview from the hematology conference and one of the themes he surfaced was increasing evidence of "emerging toxicities" related to long-term TKI treatment.  However, he didn't get into specifics.

 

Have others in our community learned more of this theme and what was shared at the conference?  Perhaps some specific findings/toxicities for each TKI?  Any new side effects / toxicities that we as patients need to be aware of?

 

Thanks for any learnings you all can share!

 


Dan - Atlanta, GA

CML CP Diagnosed March 2011

Gleevec 400mg


#2 Lucas

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Posted 19 December 2014 - 03:53 PM

Hi dan, hope everything is alright with well. Well, i read a paper from a british conference about heart problems. the long-term treatment can cause damages to the heart, specially on tasigna and there was a paper presented at ASH  - i think - that compared groups of healthy people and people with cml and we - cmlers - had 50% more chances to have a secondary cancer. I don't know if it was a large or small study, but i remember that number. I try not to worry and live my life but i also try to eat well and do exercices. i found this positive paper too :)

 

http://cml-iq.com/as...ival-tki-age-2/



#3 Jerry.s

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Posted 20 December 2014 - 05:40 AM

Wow a 50% percent chance thats huge and scary. I wonder if that's becuase of the cml or TKI medication.

#4 Lucas

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Posted 20 December 2014 - 06:25 AM

here's the paper:

 

[154] Second Malignancies Following Treatment of Chronic Myeloid Leukemia in the Tyrosine Kinase
Inhibitor Era. Själander. Background: Since continuous treatment with tyrosine kinase inhibitors (TKIs) has
dramatically improved the survival of patients with chronic myeloid leukemia (CML), it is of interest to examine
the possible risk of long-term adverse events. Previous studies have presented conflicting results regarding
risk of second malignancies. Our aim was to examine the development of second malignancies (except acute
myeloid or lymphoblastic leukemia, myelodysplastic syndromes or non-melanoma skin cancer) in CML
chronic phase patients diagnosed after the introduction of TKI treatment. Materials and methods: We
studied the development of second malignancies in 868 patients diagnosed with CML in chronic phase 2002
to 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. Each patient was
followed from the time of CML diagnosis until death from any cause, date of allogeneic hematopoietic stem
cell transplantation (SCT) or end of study on December 31, 2011, whichever came first. SCT was used as an
endpoint because of the well established increased risk of second malignancies after this procedure.
Standardized Incidence Ratios (SIR) were calculated to assess the risk of a second malignancy by dividing
the number of observed second malignancies with the number of expected malignancies in the Swedish
population, using data from the Swedish Cancer Register. The expected numbers of malignancies were
determined by dividing the CML population according to 5-year age groups, sex, region of residence (6
regions) and calendar year. The number of person-years in each stratum was multiplied with the incidence of
malignancies or deaths found in the corresponding strata in the general population. Results: With a median
follow-up of 3.7 (range 0-9.9) years, 65 (7.5%) patients developed 75 second cancers (non-hematologic), 49
of these of invasive type. Compared to expected rates in the background population matched by age, sex,
region of residence (6 regions) and calendar year, the risk of second malignancies was significantly higher in
the CML cohort, with a Standardized Incidence Ratio (SIR) of 1.5 (95 % CI 1.13-1.99). SIR before and after
the second year following diagnosis of CML was 1.6 (95 % CI 1.004-2.38) and 1.5 (95 % CI 0.98-2.11),
respectively. Looking at CML subpopulations, the increased risk of developing a second malignancy reached
statistical significance for females (SIR: 1.8; 95 % CI 1.18-1.99), but not for males (SIR: 1.3; 95 % CI 0.85-
1.91), and for patients above 60 years of age at diagnosis (SIR: 1.5; 95 % CI 1.05-1.96). Assessment of risk
by cancer type was hampered by small numbers. However, the data at hand indicate an increased risk for
gastrointestinal cancer (SIR: 3.0; 95 % CI 1.60-5.16), as well as nose and throat cancer (SIR: 37.1; 95 % CI
7.46-108.40), table 1. Conclusions: Utilizing large, population-based registries with data accumulated during
the TKI era, our results indicate that CML patients, compared to the normal control population, are at an 50%
increased risk of developing a second malignancy. Similar SIR before and after the second year following the
diagnosis of CML may indicate that these findings are linked to the CML disease itself, rather than to the TKI
treatment. Further studies and longer follow-up seem however warranted. Physicians caring for CML patients
should be aware of signs and symptoms of other malignancies in this patient population.
 
Table 1. Standardized Incidence Ratios for second malignancies (excluding cases of non-melanoma skin
cancer, AML, ALL and MDS) among 868 Swedish CML patients diagnosed between 2002 and 2011. Total
follow up time 3293 person-years (median 3.7 years).
Variable Observed Expected SIR (Observed/Expected) 95 % CI for SIR
Overall 52 34 1.5 1.13-1.99
Men 26 20 1.3 0.85-1.91
Women 26 14 1.8 1.18-2.66
Age <60 years 10 5 1.9 0.89-3.42
Age ³ 60 years 42 28 1.5 1.05-1.96
Second cancer type
Prostate 14 8 1.8 0.96-2.94
Gastrointestinal 13 4 3.0 1.60-5.16
Gynecological 4 1 3.6 0.98-9.30ASH 2014 CML report Page 8 of 29 9th December 2014
Nose and Throat 3 0,1 37.1 7.46-108.40
Lung 2 2,7 0.7 0.08-2.67
Breast 4 4,2 0.98 0.26-2.45


#5 LivingWellWithCML

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Posted 20 December 2014 - 07:16 AM

But that other paper says that we will live longer than people who don't have CML. I'm sticking with that one! :) :)

Dan - Atlanta, GA

CML CP Diagnosed March 2011

Gleevec 400mg


#6 Lucas

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Posted 20 December 2014 - 09:50 AM

But that other paper says that we will live longer than people who don't have CML. I'm sticking with that one! :) :)

 Me too, dan. me too :D



#7 Trey

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Posted 20 December 2014 - 11:05 AM

The opposite conclusion about second malignancies among CML TKI users has been reached after studying the largest group of long term Gleevec (imatinib) users, which is the IRIS clinical trial group.  IRIS trial members have taken Gleevec and follow-on TKI drugs over twice as long as the Swedish study participants (which averaged only 3.3 few years).  Also, since the IRIS group is tracked carefully and specifically as CML patients, they would seem to be more representative of the CML population.  The conclusion was that after the first 8 years of Gleevec:

 

"With >400,000 patient years of estimated imatinib exposure, the analysis of clinical safety data from clinical trials and spontaneous reports did not provide evidence for an increased incidence of malignancies for patients treated with imatinib compared to that of the general population"

 

I would put far more credence in this study. 



#8 Jerry.s

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Posted 20 December 2014 - 02:31 PM

Awesome Trey way to deliver on some. I was afraid that when my onc said most cml patients die o something else he meant another cancer

#9 Jerry.s

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Posted 20 December 2014 - 02:32 PM

Good news^^^

#10 CallMeLucky

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Posted 20 December 2014 - 09:02 PM

Statistics are fun! I'm going to suggest none of us follow this particular rabbit down the rabbit hole.
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%
 

 


#11 MACELPatient

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Posted 22 December 2014 - 01:03 PM

At my appointment a couple weeks a go my Dr alluded to Information regarding increased toxicity in the newer TKIs and how they may be going back to Gleevec for some patients as the long term toxicity is lower than the newer TKIs.



#12 chrissy778

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Posted 23 December 2014 - 10:01 AM

My Doctor told me when I was first diagnosed that people with Leukemia, the cancer stays in the blood they rarely get other cancers...That's when I was highly super aware of every feeling in my body and thought it was another cancer. I am still like that but I can be reassured more easily now. 


Its never to late to live happily ever after/ Do not squander time; for that's the stuff life is made of


#13 CallMeLucky

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Posted 23 December 2014 - 10:45 AM

Emerging toxicities and secondary cancers are not necessarily the same thing. A secondary cancer would be an extreme for an emerging toxicity. With the toxicities what you are seeing is the more powerful drugs over time are showing signs of potentially harsher long term effects. From what I have seen this is more about severity than incidence. From what I have seen its not that you have a higher risk of developing a health problem from Tasigna than Gleevec but for those who do, the problem from Tasigna may be more severe.
Numbers are a tricky thing and we should not make treatments decisions on passing studies. The most important things should be controlling the disease and quality of life. Unless there is a clear high risk I think trying to project what the risk variance between two drugs over a decade will be is a little unrealistic.
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%
 

 


#14 Lucas

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Posted 23 December 2014 - 09:37 PM

I agree with trey. as i said, i don't know the reability of the research and i was aware about the iris trial results. as lucky said: numbers are a tricky thing. 



#15 Billie Murawski

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Posted 23 December 2014 - 11:34 PM

Hi Everybody,

      How the heck do I put a post up on this new software?

I'm finally back on line but I don't know how to tell anyone.

                                                              Billie



#16 gerry

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Posted 24 December 2014 - 12:16 AM

Hi Billie,

 

Welcome back, everyone has been asking after you. Hope all is well with you and Ron. :)







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