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Poor CML response to imatinib, dasatinib

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9 years 5 months ago #223 by iCMLf
Dear Colleagues,

I would greatly value your thoughts a female patient.

Presented in summer 2012, age early 60s, with weight loss and progressive fatigue. Spleen enlarged 18cm bcm Hb 78, WBC 346 (24 basophils, absolute count), platelets 733. Bone marrow showed CML in chronic phase, cytogenetics showed Ph only, QPCR was 432%. She had a couple of weeks of Hydroxyurea while the diagnosis was being established, then had imatinib 400 for 10 weeks, getting eventually very unpleasant cutaneous problems. At that point she had a spleen still just palpable, and haemoglobin 113, total white count 6.5 and platelets 173. QPCR was 226%.

She switched to dasatinib 100 which has been well tolerated. After a further 8 weeks she has no palpable spleen, Hb 104, WBC 7.2, platelets 168. However QPCR is unchanged at 231%. We have screened for mutations in the ABL kinase domain and found none.

So, high risk CML, 2 months of imatinib, not tolerated and although got haematological remission, no molecular response. 2 further months of treatment with Dasatinib, well tolerated, but no molecular response.
Would you think she should try Nilotinib, or compassionale access for Ponatinib, or start investigating transplant?

Many thanks for your thoughts.

Best wishes, Peter
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9 years 5 months ago #224 by tim
Dear Peter,

Assuming she is CP at diagnosis, I agree the lack of molecular response is very worrying but I am not sure it is time to switch just yet. The fact that she has achieved CHR after 2 months of dasatinib makes me hopeful that molecular response may become evident over the next few months. If you assume that compliance may have been poor, or therapy quite interrupted while she was on imatinib, then her response to dasatinib may be expected to be more like that of an untreated patient. In that case her molecular response to dasatinib may take more than 2 months. We often see patients who have little or no molecular response at 2 months but very good responses after 3 months.

I would continue monthly blood RQ-PCR and I would also repeat the marrow looking for clonal evolution and other features of transformation.

If there was clonal evolution OR a failure to get below 10% BCR-ABL after another 2-3 months then I would make a strong case for ponatinib and start considering a non-myeloablative allograft. I don’t think nilotinib (or bosutinib) is likely to be any more effective than dasatinib in this case.

I would of course be interested in other views on this case.

Regards
Tim
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9 years 3 months ago - 9 years 3 months ago #254 by Trey
I would prefer to correlate PCR with FISH results until CCyR is achieved.

Trey
CML Patient Advocate
USA
Last edit: 9 years 3 months ago by Nicola.
  • Michele Baccarani
  • Michele Baccarani's Avatar
9 years 3 months ago #261 by Michele Baccarani
Replied by Michele Baccarani on topic Re: Poor CML response to imatinib, dasatinib
Agree with Tim's comments, basically, that it is a bit too early to change the treatment. I’m curious about the methods of the lab where PCR was performed.
A ratio of 432% baseline is uncommon, as it is a ratio of 226% in a patient in CHR. Apart from controlling the molecular response more frequently, every month, why not looking at the karyotype? If you do not want, or cannot, take marrow cells, do FISH on peripheral blood. With a BCR-ABL ratio of more than 100, I’d expect about 100% of nuclei BCR-ABL positive. A word on mutational analysis. Mutations are rare baseline, but this a case of a patient in accelerated phase (basophils more than 20%) who may be worth of a mutational analysis.

Best regards, Michele Baccarani
  • Jeff Lipton
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9 years 3 months ago #263 by Jeff Lipton
Replied by Jeff Lipton on topic Re: Poor CML response to imatinib, dasatinib
I agree with Tim about waiting a little longer, but not much longer. If by 3-4 months there is no molecular response, I think the writing is on the wall. Nilotinib post dasatinib in this scenario, is not likely to work and if it does, the response is short-lived at least according to the MDA data. Ponatinib is an option for a quick look to see if there is a response, but in the meantime the option for a RITC allograft should be explored if possible.
  • Deepak K Mishra
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9 years 3 months ago #267 by Deepak K Mishra
Replied by Deepak K Mishra on topic Re: Poor CML response to imatinib, dasatinib
A ratio of 432% at baseline is unheard of. I look at it as pretty interesting. I presume that the cABL amplification has been optimum. In my practice I had baselines above 100%, 140%, 125% , even 165% in that range. I explain it by the presence of two bcr-abl1 transcripts per cell. Its like 2 Ph chromosomes in conventional karyotypinf / FISH signals.
Am I right in thinking so !!!! Any other opinions on this.
Regards.
Dr. Deepak K Mishra,
Tata Medical Centre, Kolkata, India.
Moderators: Melissa Davis-Bishop