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Reply: 24 Y Female | CML-AP - 11 Yr | 3 TKI+ (T315I Mut.) | Treatment after Ponatinib


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Topic History of: 24 Y Female | CML-AP - 11 Yr | 3 TKI+ (T315I Mut.) | Treatment after Ponatinib

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  • Michael Deininger
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1 year 6 months ago
24 Y Female | CML-AP - 11 Yr | 3 TKI+ (T315I Mut.) | Treatment after Ponatinib

NEW RESPONSE – Mike Deininger

Here is my recommendation:

First of all bmbx to assess disease phase.

 If blasts <=15% proceed to haplo from mother asap. Fifty-seven years of age should be fine. Continue ponatinib up to 5 days prior to bmt and resume at 15mg post bmt upon count recovery
 If blasts >15% consider giving 1 cycle of FLAG-Ida and stand by to proceed with bmt from mother in case of prolonged myelosuppression. I don’t think there is clear-cut data to support this, so needs to be discussed with patient in this way.

I am not aware of any therapy that would address the ASXL1 mutant clone. One could consider adding 5-aza, but I would worry this may delay BMT without gaining much.

  • jeff lipton
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1 year 6 months ago
24 Y Female | CML-AP - 11 Yr | 3 TKI+ (T315I Mut.) | Treatment after Ponatinib

I think that you can play around with unproven possibles such as combination chemo, but in the long run the only really possible cure is an allograft. You do not want to wait until you have blast crisis. I would use the brother and there are ways to overcome DSA incompatibility. There is a lot of controversy as to whether a younger unrelated donor who is matched as well as a full sibling match is better, but most of us who transplant will take the best match if possible. If the sib is too much of a risk because of a high DSA, then there is no question to use either of the parents if the match. They are not old when it comes to being a donor.

  • Vivek Kumar
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1 year 6 months ago
24 Y Female | CML-AP - 11 Yr | 3 TKI+ (T315I Mut.) | Treatment after Ponatinib

*** Reports Updated, Urgent Final Responses Required ***

Treatment 6:

BCR_ABL: 20% [August 2022]
Medication: Ponatinib 45 mg [June 2020 - Ongoing] + Interferon 90mcg (for once for 2 weeks, discontinued due to serious breathlessness and depression signs)
Mutation:
T315I - ABL1 Mutation [May 2020] (Missense) [Variant Allele Frequency - 35.8%] (coding: c.944C>T)
E705* - ASXL1 Mutation [Detected August 2022] (Nonsense) [Variant Allele Frequency - 34.51%] (coding: c.2113G>T)

CBC:
Hb: 11.7 (bio ref: 12-15)
TLC: 3200 (bio ref: 4000-10000)
Platelets: 150000 (bio ref: 150000 - 410000)

Peripheral Smear Test:
(N: 64, L:23, M:12, E:01) (No atypical cell/parasite seen)

ONGOING: Ponatinib 45 mg. (Daily)

Questions:

1. Is there any treatment to fight ASXL1 Mutation in CML-AP? Along side T315I mutation?

2. We can do ahead with parents half match transplant, if Sibling still has DSA strongly positive. But doesn't longer survival depend on having stem cells from younger donors?
What is a suggested donor here? Brother (27 Years Old) or Mother (hypertension and 55 Years old) or Father (Diabetic and 61 Years Old)

3. Requesting everyone reading to please suggest their final response or it, it would be a great help.

Thanks,
Vivek

  • Giuseppe Saglio
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1 year 9 months ago
24 Y Female | CML-AP - 11 Yr | 3 TKI+ (T315I Mut.) | Treatment after Ponatinib

This is a very difficult situation. I substantially agree with Tim who suggested to try also the combination of ponatinib and asciminib. I wonder also if a short course of chemo AML like (FLAG or FLA-IDA) could help to restore at least in part the sensitivity to ponatinib or asciminib after recovery from aplasia. This type of chemo could also decrease the titer of DSA antibodies, facilitating a subsequent transplant, that in any case remains the final solution. Substantially I would treat this case as a Ph-positive AML (or CML BC) using TKIs before and after the transplant.

  • Michael Deininger
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1 year 9 months ago
24 Y Female | CML-AP - 11 Yr | 3 TKI+ (T315I Mut.) | Treatment after Ponatinib

I agree with the assessment of Dr. Hughes. This patient is high risk and given her age an allogeneic stem cell transplant is the preferred option. My additional thoughts are as follows:

1) The last data are from May 2020. I recommend to repeat the BCR-ABL1 qPCR, BCR-ABL1 mutation screen, and do a bone marrow biopsy with cytogenetics. It will be important to know the variant allele frequencies of all mutations detected. If there was indeed a compound mutation combining T315I with another mutation, then a combination of ponatinib and asciminib may work.
2) For the haploidentical transplant she should be de-sensitized prior to transplant. This is not my area of expertise. However, this paper bloodbook-2017-645.pdf was written by transplanters from Hopkins who have deep expertise on haploidentical transplants, and I would personally follow the proposed protocol. You could preemptively collect autologous stem cells for a rescue to cover your base.

  • Tim Hughes
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1 year 9 months ago
24 Y Female | CML-AP - 11 Yr | 3 TKI+ (T315I Mut.) | Treatment after Ponatinib

This young woman has not responded to imatinib, nilotinib, dasatinib ponatinib and was intolerant to bosutinib. Her resistance is very likely both BCR::ABL1 dependent (T315I plus M351T) and BCR::ABL1 independent. A bone marrow aspirate to look for evidence of transformation to blast crisis would be reasonable at this stage. The prospect of gaining a molecular response to asciminib is quite low, given the long term failure to response and especially the lack of response to ponatinib. However given its low toxicity and apparent availability a 3 month trial of asciminib 200 mg twice daily would be reasonable while you sort out the allograft options.

If, as expected, there is minimal molecular response to asciminib by 3 months, I would look at the best available allograft donor and proceed down that pathway. If a suitable donor cannot be identified, the only other option would be to try the combination of ponatinib and asciminib in the hope that the main driver for resistance is the T315I mutation combined with another mutation which may be responsive to the combination. This is based on in-vitro data from Michael Deininger and Chris Eide and they may be able to provide better guidance as to whether this would be a reasonable approach, what doses to use, and whether there is any clinical data to support this approach. I personally don’t see much value adding interferon to the ponatinib, although I am aware of anecdotal evidence that it can sometimes play a role in the resistance setting.

I welcome other opinions about this very challenging casa.