Treatment Options Requested:

24 Y Female with Ovarian Cyst (Recurring) - NEW DELHI, INDIA

Diagnosed Year: 2010 (CML-CP) - Aged: 11 Years
Progression Year: 2019 (CML-AP) - Aged: 20 Years

Patient was on Imatinib for the last 9 years, but after mutation [2019] that stopped working.
She was then switched to Nilotinib, then Dasatinib, with further mutation detected (T315 I MUTATION) in 2019. Patient never achieved BCR-ABL IS% less than 10 in entire treatment journey.

Treatment 1:

BCR_ABL: 83% [April 24th 2011]
Medication: IMATINIB [2010-2019]
Mutation Detected: M35IT

Treatment 2:

BCR_ABL: 45% [August 12th 2019]
Medication:: Nilotinib (800) [June 2019 -August 2019]
Mutation Detected: M35IT

Treatment 3:

BCR_ABL: 19.43% [February 19th 2020]
Medication: Dasatinib [September 2019 February 2020]
Mutation Detected: M35IT
Reason: I/v/o no response to Nilotinib, therapy
was switched to Dasatinib.

Treatment 4:
BCR_ABL:
Medication: Bosutinib(500) [2-10th March 10th 2020]
Reason: Patient c/o severe diarrhea after a week
and was switched back to Dasatinib i/v/o
poor tolerance.

Treatment 5:
BCR_ABL: 23.23% [Oct 2020]
Medication: : Ponatinib 45 [June 2020 - Ongoing]
Mutation: T315I [May 2020]


BCR-ABL IS% has been ranging between 15% to 30% [Latest: 30% June 2022], sometime it goes down, sometimes increases.

Treatment Options Given to us:

1. Ponatinib 45mg + Interferon 90mcg (Once a week)

Caregiver Question: We know she is heavily treated, but will adding Interferon once introduced can't be stopped, if we have got good MR, or is it a good combination to explore in long term?

2. ASCIMINIB 200

Caregiver Question: We do have this through clinical trails, but currently we don't have any large INDIAN patient data for this, our doctors are skeptical this medicine, given patient is so resistant to all other treatment.


3. BMT

Situation: We don't have (10/10) match, either in family or MUD right now.
Half-Sibling Match (5/10) with brother but with very high DSA POSITIVE TEST

HLA ANTIBODIES CLASS I & CLASS II: 10941 & 5605

Mother & Father - 60+ OLD (both half match as well)

Caregiver Question: We really want to go for BMT, but given high DSA, rejection chance and GvHD chances, is there any new ways to counter this, which has very HIGH SUCCESS RATE? Will it still outweighs than trying treatment option 1&2?

Why has Ponatinib Failed? Any Mutation or anything we should check to confirm?


GIVEN OUR ABOVE SCENARIO, REQUESTING YOUR COMPLETE RECOMMENDATION, any other options, opinions please?

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.

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.

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.

*** 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

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.