Location : Sweden

A 29 year old woman diagnosed with CML in CP Sokal intermediate June 2018, started on Imatinib, after 3 months Nilotinib, but after 1,5 years BCR-ABL varying 0,3-0,6% and transferred to us. May 2020 Ponatinib started and preparations for allotransplant. Cytogenetics with one extra aberration, low platelets and blasts 6% after 4 months on Ponatinb, BCR-ABL-mutations negative, but just before transplant a E255V-mutation was found. Allo URD sept/2020.   

6 months post-transplant BCR-ABL = MR4, GVH skin and immunosuppressive treatment. (In retrospective - was it really GvH or rather Ponatinib side effects?) BCR-ABL increased to 64%. The cytogenetics no extra aberrations, just Ph+.Immunosuppression tapered and Asciminib started (CUP) 12 months post-allo. (Sept 2021) There was a prompt effect  MR3 after 3 months and DMR after 6 months, but 9 months after start of Asciminib BCR-ABL was increasing, Cytogenetics Ph+ and E255V mutation. DLI was given sept/2022 and oct/2022, Asciminib increased to 80 mgx2.  BCR-ABL rising and 6 % blasts in marrow. No GvH. Asciminib increased to 200mg x 2.A 3d DLI in december 2022 . Developed a GvHD in colon, skin, mouth and liver. Continued Asciminib and in May 2023 MMR. (Only hospitalized 10 days).

One year later, december 2023 the BCR-ABL 1%. Ponatinib 30 mg was added and the process of a second allo URD was started. E255V-mutation and 2 additional unknown mutations. On the combination Ponatinib 30 + Asciminib 200x2 reached MMR in Feb 2024, but  just before admission for allo BCR-ABL = 0.17%. Second allo URD with new donor 25 /April/ 2024, started Asciminib 6 weeks posttransplant, 2 months post-allo BCR-ABL 0,023% and 3 months post-allo 0,76% 2% recipient T-cells and 8% recipient CD34pos cells in marrow, all the time cytopenic needing G-CSF.  Asciminib was increased 200 mg x 2 and ponatinib 30 mg was added. 4 months post allo immunosuppression was stopped and BCR-ABL > 10%, cytopenic no GvH and asciminib 200 mg x 2 and ponatinib 30 mg, both were stopped and Started Olverembatinib in a patients named program 30/oct/2024 at that time bone marrow 4,5%blasts, Ph+, and BCR-ABL>10% .And know after 4 weeks on Olverembatinib myeloid blast crisis, with 20-25% blasts.

What can we do for this patient? Combine Olverambatinib and Asciminb? Start Azacytidine + Venetoclax and then DLI? Interferon in hope to find a GvL effect? Homoharringtonin? Other immunotherapy?Do you have other ideas? The patient (35 years old) is willing to do everything to have more treatment. Do you know of any clinical studies? 

This is an unfortunate horrible case. This poor woman has failed 2 allografts with different donors and DLI, GVH with presumed GVL, multiple TKIs including combination PON/ASC. Without second guessing, should immunosuppression have been pulled earlier and GVH untreated longer. Who knows? I know the treating physician wants to do more, but with what end in mind? SCT is not recommended for BC-CML because it does not work. Neither will DLI at that stage even with IFN priming. The chemo suggested may control the disease for a short period of time but a cure is not on the table. The treating physician has gone beyond what could normally be expected by anyone or even possible by most of us, and should not have guilty feelings that they missed something. We forget that sometimes we lose the battle through no fault of our own. Patient needs a talk about futility and what to expect. Any study out there would likely be phase 1 or 2 and not curative. Any form of palliative therapy that works is appropriate.

It is hard to find in my memory and files a case receiving this level of professional care. They already did everything that was/is considered active in a case like this. Including 2 alloSCTs, including all efforts to exploit an host immune reaction against leukemia. Now and for the first time the disease progressed to advanced phase disease. Probably I'll be the only one or one of the few surrenders: there is no reason to be "aggressive" because we'll induce acting this way a bad QOL for the rest of the (short) life of this young pt. Moreover, since the disease is partially/totally outside the control of BCR::ABL1, insisting with any other TKI is not a clever idea because the pressure on the (residual) BCR::ABL1 cell population will favour the life of more aggressive leukemic cells (yes, our last resource is the residual CP disease). So, my first option would be hydrea and supportive care, the second option, one cycle of Aza/Veneto....
A surrender physician in front of a 35 yrs old pt is currently not perceived as a "good doctor" but this is my position in front of this case. With a sad heart.

I suggest olverembatinib 30mg QOD + AZA +/- Ven (14 days). I conducted a study in CML-MBP patients receiving this regimen. The response rate was 70%, even in those who failed olverembatinib monotherapy. Adding Ven will increase the response rate, but more BM suppression.

This is a very tragic situation. The physician has done absolutely everything they could for this patient, but the patient has relapsed again with blast phase CML following a second allograft. Although the patient is still very young, I believe the focus should be on optimising quality of life for the short time the patient has. I would discuss with the patient hydroxycarbamide and ven/aza as options. Given the extensive treatment the patient has had already, I think any benefit from ven/aza over hydroxycarbamide would be limited if there was any benefit at all, and it would result in more hospital visits and potentially more side effects. Like Professor Rosti, I think my preferred option would be hydroxycarbamide and involvement of the palliative care team to optimise symptom management and provide additional support.

Azacytidine + Venetoclax alongwith DLI and Olverembatinib should be the next option as TKI alone wouldn't be able to harness this aggressive disease