‘A Case Conversation for your interest. We welcome your comments and any further questions on the case discussion below...'

1) Andrew Wei: 
I have a 45 yo lady with CML-CP; baseline WCC141. Platelets at baseline were 444 but went up to 1000 in 2 weeks.
Sokal 0.92 (int) using platelets of 444 Hasford 629 (low) Eutos 33 (low)


The CG report showed: All cells analysed contained a reciprocal 9;22 translocation.
She was commenced on dasatinib 100mg daily.
Baseline b2a2 146%
At 4 months 35%
At 7 months 7%
At 9 months 24%, with no mutations detected after a 1 week interruption

She has had 2 episodes of intercurrent infection resulting in pancytopenia (including neutrophils <0.5) needing transfusions and necessitating dasatinib interruption for a total of 4 weeks. She now has a normal WCC but a platelet count of 1000 again.
In the absence of mutations, would you consider keeping her on TKI or switching? Her drug adherence has been excellent, as far as we can tell.
At what point would you consider a MUD allo for this lady? No sibs.

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2) Tim Hughes: She has had a remarkably poor response to dasatinib. I presume her platelet elevation means she has lost haematological response (unless she has a co-existent Jak+ clone). This puts her at high risk of progression. A marrow may be useful at this stage to look for clonal evolution and exclude blast crisis. Your options are:
a) Increasing to 140 mg Dasatinib. Unlikely to make a difference and will probably worsen cytopenia


b) Switch to nilotinib 400 mg bd. also unlikely to achieve a worthwhile response but may be useful while you find a better option. 


c) Bosutinib may also be available to you locally but rarely works in dasatinib resistant patients. 


d) Ponatinib actually may achieve a molecular response here. The problems are the cost and the high risk of vascular events. If her risk profile for vascular events is not high, this may be your best option.

It remains quite likely that you will need to proceed to an allograft, unless you do achieve a molecular response to one of these options in the next 3-6 months so you should get things moving to find a donor.

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3) Andrew Wei: Thanks for your suggestions. 
Are there additional tests e.g. pCrk that you still do that may be informative? The marrow is a good idea, which I will do. It will also allow us to reassess the karyotype and do a JAK2 mutation test.

In the absence of an in vitro test guiding treatment, would the simplest option be to increase the dose of dasatinib and plan allograft? If neutropenia becomes an issue, do you consider G-CSF safe in CML? Is there any role for adding IFN? 



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4) Tim Hughes: Yes we could look at the level of in vivo kinase inhibition being achieved. We could also test her blood cells for sensitivity to the various TKIs. These are still a research test - not validated but potentially useful. We could also do high sensitivity mutation testing but not sure the yield would be high here.

I don't see much value in adding interferon here. 



I would have no hesitation using G-CSF to enable you to maintain dose intensity. 



You could certainly try higher dose dasatinib but you may have a better response to nilotinib. This is where the sensitivity studies may be helpful. It is frustrating that ponatinib is still difficult to access. 



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5) Susan Branford: We could do sensitive mutation analysis on this patient I believe she was off dasatinib when last tested, but only for a week. We do know that some mutations can be rapidly deselected in the absence of inhibitor so it may be worthwhile repeating the mutation analysis while on TKI. We can perform sensitive mutation analysis if we receive a new sample and on the sample collected in September. Just need the same sample as required for quantitative PCR for BCR-ABL or RNA.

Follow up: We did not detect mutations by direct sequencing or using sensitive mass spectrometry.

6) Deb White: Following sample analysis your patient appears to exhibit a degree of sensitivity to dasatinib in both the in vitro and in vivo tests. However, after 9 months of dasatinib therapy we certainly wouldn't expect to see any p-Crkl present so this is concerning.

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7) Andrew Wei: The bone marrow did not show accelerated disease. Awaiting karyotyping. Her blood counts are now normal.

8) Tim Hughes: I guess the things that are still pending (or you may have) are the cytogenetics, JAK mutation screen, dasatinib level, and sensitive BCR-ABL mutation screening. The drug sensitivity studies were of limited value because we could only test dasatinib due to limited cells in the sample received. However there is evidence of response and the IC50 to dasatinib is in the normal range, so while waiting for more information I agree that dasatinib 140 mg/day would be reasonable now that her counts are OK. You may have to use G-CSF and tolerate platelet counts down to 30 in the short term.

Let’s see if there is any improvement on the higher dose dasatinib. I would monitor response with RQ-PCR monthly at this stage. If there is no significant improvement over the next 2-3 months I would consider either switching to ponatinib or proceeding with an allograft.

Agree with previous remarks
ponatinib may be best result in the short run, but MUD donor needs to be found and allograft considered.
unlike anything else will give you a durable response if any


(case repeated here for reader reference)

‘A Case Conversation for your interest. We welcome your comments and any further questions on the case discussion below...'

1) Andrew Wei: 
I have a 45 yo lady with CML-CP; baseline WCC141. Platelets at baseline were 444 but went up to 1000 in 2 weeks.
Sokal 0.92 (int) using platelets of 444 Hasford 629 (low) Eutos 33 (low)


The CG report showed: All cells analysed contained a reciprocal 9;22 translocation.
She was commenced on dasatinib 100mg daily.
Baseline b2a2 146%
At 4 months 35%
At 7 months 7%
At 9 months 24%, with no mutations detected after a 1 week interruption

She has had 2 episodes of intercurrent infection resulting in pancytopenia (including neutrophils <0.5) needing transfusions and necessitating dasatinib interruption for a total of 4 weeks. She now has a normal WCC but a platelet count of 1000 again.
In the absence of mutations, would you consider keeping her on TKI or switching? Her drug adherence has been excellent, as far as we can tell.
At what point would you consider a MUD allo for this lady? No sibs.
2) Tim Hughes: She has had a remarkably poor response to dasatinib. I presume her platelet elevation means she has lost haematological response (unless she has a co-existent Jak+ clone). This puts her at high risk of progression. A marrow may be useful at this stage to look for clonal evolution and exclude blast crisis. Your options are:
a) Increasing to 140 mg Dasatinib. Unlikely to make a difference and will probably worsen cytopenia


b) Switch to nilotinib 400 mg bd. also unlikely to achieve a worthwhile response but may be useful while you find a better option. 


c) Bosutinib may also be available to you locally but rarely works in dasatinib resistant patients. 


d) Ponatinib actually may achieve a molecular response here. The problems are the cost and the high risk of vascular events. If her risk profile for vascular events is not high, this may be your best option.

It remains quite likely that you will need to proceed to an allograft, unless you do achieve a molecular response to one of these options in the next 3-6 months so you should get things moving to find a donor.
3) Andrew Wei: Thanks for your suggestions. 
Are there additional tests e.g. pCrk that you still do that may be informative? The marrow is a good idea, which I will do. It will also allow us to reassess the karyotype and do a JAK2 mutation test.

In the absence of an in vitro test guiding treatment, would the simplest option be to increase the dose of dasatinib and plan allograft? If neutropenia becomes an issue, do you consider G-CSF safe in CML? Is there any role for adding IFN? 



----
4) Tim Hughes: Yes we could look at the level of in vivo kinase inhibition being achieved. We could also test her blood cells for sensitivity to the various TKIs. These are still a research test - not validated but potentially useful. We could also do high sensitivity mutation testing but not sure the yield would be high here.

I don't see much value in adding interferon here. 



I would have no hesitation using G-CSF to enable you to maintain dose intensity. 



You could certainly try higher dose dasatinib but you may have a better response to nilotinib. This is where the sensitivity studies may be helpful. It is frustrating that ponatinib is still difficult to access. 


5) Susan Branford: We could do sensitive mutation analysis on this patient I believe she was off dasatinib when last tested, but only for a week. We do know that some mutations can be rapidly deselected in the absence of inhibitor so it may be worthwhile repeating the mutation analysis while on TKI. We can perform sensitive mutation analysis if we receive a new sample and on the sample collected in September. Just need the same sample as required for quantitative PCR for BCR-ABL or RNA.

Follow up: We did not detect mutations by direct sequencing or using sensitive mass spectrometry.

6) Deb White: Following sample analysis your patient appears to exhibit a degree of sensitivity to dasatinib in both the in vitro and in vivo tests. However, after 9 months of dasatinib therapy we certainly wouldn't expect to see any p-Crkl present so this is concerning.
7) Andrew Wei: The bone marrow did not show accelerated disease. Awaiting karyotyping. Her blood counts are now normal.

8) Tim Hughes: I guess the things that are still pending (or you may have) are the cytogenetics, JAK mutation screen, dasatinib level, and sensitive BCR-ABL mutation screening. The drug sensitivity studies were of limited value because we could only test dasatinib due to limited cells in the sample received. However there is evidence of response and the IC50 to dasatinib is in the normal range, so while waiting for more information I agree that dasatinib 140 mg/day would be reasonable now that her counts are OK. You may have to use G-CSF and tolerate platelet counts down to 30 in the short term.

Let’s see if there is any improvement on the higher dose dasatinib. I would monitor response with RQ-PCR monthly at this stage. If there is no significant improvement over the next 2-3 months I would consider either switching to ponatinib or proceeding with an allograft.