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Any role for chemotherapy in TKI refractory CP-CML

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Andrew Shearer
Topic Author

6 years 10 months ago #1170 by Andrew Shearer

Any role for chemotherapy in TKI refractory CP-CML was created by Andrew Shearer

I have a 64 yr old female patient diagnosed with standard intermediate risk(sokal 0.6) CML early 2012.
She has never achieved any significant PCR response,(rarely <20%) despite cycling through all available TKIs, some more than once. Best response has been recently with ponatinib since april 2015 and pegylated interferon late 2016; down to 6.6%. Unfortunately she is now experiencing significant vascular side-effects from Ponatinib, exertional angina; TIA, retinal occlusions; so I am planning to change back to dasatinib, which was the better tolerated of the TKIs, and did show some response down to 12% on PCR; after 8 months of therapy.
Previous testing for mutations of the Philadelphia chromosome have been negative.
The option of allogeneic transplant has been discussed on several occasions, but patient has declined that option as recently as last September.
I have been considering giving this patient Induction-type chemotherapy in the hope of reducing the stem cell pool to a level that ongoing oral therapy may be able to control.
Any other thoughts or options including any specific tests you would recommend on repeat marrow other than mutational analysis; cytogenetics

Tim Hughes
Topic Author

6 years 10 months ago #1171 by Tim Hughes

Replied by Tim Hughes on topic Any role for chemotherapy in TKI refractory CP-CML

I guess these are your options:
1. Allograft. I can understand her reluctance – 30% TRM in this age group. Hard to justify while she is partially responsive to TKI therapy.
2. Ongoing dasatinib and pegINTRON. Since you have achieved some level of cytogenetic response (I assume based on the PCR value but worth checking the marrow cytogenetics – you may find evidence of clonal evolution which may change the risk profile somewhat) there is some evidence that these patients are not as poor risk as patients who are either not taking a TKI or have no evidence of cytogenetic response.
3. ABL001 – the allosteric inhibitor which is available in the Phase I study. I haven’t been impressed with responses so far in patients with pan-resistant disease, but it is a relatively safe option – probably worth considering.
4. Chemotherapy. We tried this in TIDEL I as have others (e.g the HOVON group). No convincing evidence that it is beneficial in CP CML in any setting.
5. Omacetaxine. It is available in this setting I think but I can’t see any advantage over the current approach unless you lose response.
6. Hydroxyurea – only as palliative therapy if all other options exhausted.

Jeff Lipton
Topic Author

6 years 10 months ago #1172 by Jeff Lipton

Replied by Jeff Lipton on topic Any role for chemotherapy in TKI refractory CP-CML

It is not clear from the request what the patient wants! Although Tim provides a number of options which may or may not be available to her, they are generally all experimental and given her degree of resistance to previous therapy, likely not going to get long term durable responses. Intensive chemotherapy may debulk her, but in the long run TKI sensitivity would be necessary for long term control.
The option of allografting if an appropriate donor is available is really the only approach that may give her long term survival. I am not sure that the 30% TRM is necessarily the case at a good center, but obviously the potential for morbidity is significant. Morbidity may be reduced with significant immune suppression such as is used with haplo transplants, but at the expense of relapse.
The only other option is as Tim says, palliation with HU.

Jorge Cortes
Topic Author

6 years 10 months ago #1173 by Jorge Cortes

Replied by Jorge Cortes on topic Any role for chemotherapy in TKI refractory CP-CML

In a setting such as this one has to adjust the expectations to those of the patient. SCT would be most appropriate but if the patient does not want that then the best option is investigational (if able to get to ABL001). If not, I would go with a TKI aiming for some control acknowledging that we will not achieve the deepest response. I am assuming that imatinib, dasatinib, nilotinib, bostuinib and ponatinib have all been tried (dasatinib, ponatinib are specifically mentioned in the narrative). I would continue the best tolerated agent. It has been shown that some control is better than hydroxyurea only, and that even a minor cytogenetic response confers a survival benefit compared to no cytogenetic response; not as good as complete cytogenetic response of course, but better than what you can expect with hydroxyurea only. Omacetaxine is a good option if available. This is the kind of scenario where it is worth trying as you can get some patients to respond. Otherwise, I am no fan of chemotherapy.

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