Indeed challenging. Would a trial of another second generation TKI like Nilotinib not be useful? He is not a failure as 3 month BCR::ABL RQPCR is 2 %.
Was there any myelofibrosis in BM?

Yes this is an unusual and difficult case. I am worried that this young man is one of the 2-3% of CML patients who develop profound cytopenia and little or no response to their TKI therapy. However his molecular response at 3 months was actually reasonable. I guess there is still a small chance that you will be able to steer through this difficult phase and get some level of response with modified dose dasatinib or another 2G TKI. It has already been 7 weeks with no therapy and looks likely to be a lot longer – this puts him at high risk of transformation. I’m not sure asciminib is a better option at this stage – it has a similar problem with thrombocytopenia as dasatinib has, perhaps less neutropenia and anaemia. Given that he has gone for 6 months with minimal response, it would also be worthwhile to check for a kinase domain mutation.

Given his age and presumed fitness I would be getting prepared to go ahead with an allograft in the next 3 months if the situation doesn’t improve (i.e count recovery and some evidence of molecular response back on TKI therapy). I think if you can’t deliver effective TKI therapy for a prolonged period despite growth factors then an allograft would be the best option – if a suitable donor can be found.

Thank you for your insights. I have been discussing this case with Sarah and suggested that she post it here to gather advice from a broader group as there is likely more experience with adult patients.

As Sarah mentioned, G-CSF has been administered but has not shown efficacy thus far. Romiplostim has also been considered. There are a few case reports of aplastic anemia associated with dasatinib. The key question is how long we should wait before determining whether this is indeed AA, rather than the transient count suppression often observed with dasatinib, which is typically reversible.

Another question is whether it would be safe to introduce asciminib in this context, given the rising BCR::ABL1 level. If this is irreversible, then, he needs HSCT, and he needs disease control while awaiting HSCT. While asciminib poses a lower risk of count suppression compared to ATP-competitive TKIs, its effects in this particular situation remain uncertain.

We greatly appreciate any further thoughts or suggestions.

Nobuko Hijiya
Pediatric Oncology
Columbia University

This is not a usual case with early occurrence of profound bi-cytopenia linked to dasatinib (I presume that viral or other toxic causes were excluded); the determination of the concentration of dasatinib in the blood could have given some indication at that time. It seems that there is no progression of the disease to the advanced phase. I suggest discontinuing dasatinib until ANC > 1.0 x 10^9/L and platelet count > 50 x 10^9/L and then resume at a lower dose. Meanwhile, growth factor support can be used.

My best wishes for the boy's prompt recovery.

With additional information provided by Dr Harney (in brackets):

This is a complicated case. It would be useful to have additional information on:

1) height and weight of the boy at diagnosis to calculate the body surface area and to calculate an appropriate dasatinib dose (60 mg/m2 with a maximum dose 100 mg - once daily),

(Ht 183 cm, Wt 64 kg – BSA 1.84 m2)

2) size of the spleen at diagnosis and during treatment

(He had massive splenomegaly at diagnosis (border not palpable as it extended into the pelvis, measured 30cm on imaging at diagnosis). By 2 months into treatment, the spleen was no longer palpable. Currently the spleen is mildly enlarged on exam ~3cm below LCM, obtained US this weekend for more precise measurement and the spleen is currently measuring 16cm in length on US, so moderately enlarged.)

3) calculation on any risk score (Sokal, Eutos) at diagnosis

(High risk by Eutos (8% basophils and spleen >15cm below LCM); intermediate by Sokal (2% myeloblasts, normal platelets at dx))

4) karyotyping at diagnosis showing any additional chromosomal aberrations (ACA) as risk factors

(No ACAs)

5) The presently applied threshold for the platelet count resulting in platelet transfusions every 2 - 3/x a week.

(Transfusing platelets are <10 k/mcl)

It is highly probable that this is dasatinib toxicity because treatment was initiated with the maximum recommended dose. A nice hematological response was observed at month 1, but the marrow suppressing activity of dasatinib was possibly underestimated. I wonder how frequently whole blood cell counts were performed in the interval from month 1 to month 3 as the profound cytopenia is described as a sudden event at month 3.

(Initial platelet nadir occurred 1/31/25 (plt 67)- was checking labs twice weekly at that time. Observed spontaneous platelet recovery by 2/12/25 (plt 167) and spaced labs to weekly – plt 321 on 2/21 then 176 on 2/28. Hemoglobin was steadily uptrending at each weekly check and ANC normal ~3000. After 3 weekly normal CBCs, I spaced the labs to monthly at which point I noted the “sudden” drop. In hindsight, I of course wish I had checked more frequently in that month.)

I would suggest administering G-CSF as a first step to increase the neutrophils and in parallel the platelets might also increase. I do not have experience with TPO agonists in this scenario. SCT is not an option presently.

(I started GCSF on Thursday 5/29 so he has seen 3 daily doses of 5 mcg/kg and ANC has not improved yet, but I am planning to observe on GCSF for about 10 days and if no improvement at that point consider another bone marrow evaluation.)

Follow-up questions from Dr Harney -

1) What do you make of his current moderate splenomegaly and how that may be playing into his pancytopenia? His response to platelet transfusions is lower than I expect (example 7 k/mcl à 16 k/mcl yesterday after 1 unit of pheresed platelets which is typical of his recent responses) which is concerning for sequestration. He has no bleeding symptoms and is otherwise clinically well. Is there anything I can do to manage the hypersplenism?

2) Can you elaborate on why you advise that SCT is not an option presently? I have been getting mixed opinions from BMT colleagues (we do not do pediatric BMT at my institution, so would have to refer out for transplant).

Thank you for your thoughtful insights into this difficult case!

16yo M presented 1/2025 with WBC 554 k/mcl, Hgb 7.7 g/dl, Plt 251 k/mcl. No blasts in PB or marrow by flow cytometry. BCR/ABL FISH was positive. Started on dasatinib 100mg once daily for treatment of chronic phase CML. Initial count nadir about 3-4 weeks into treatment (plt nadir 67k, normalized to 300s without any dose adjustments or medication hold, ANC remained normal). At 3 month lab check in early April, found to have profound cytopenias with ANC 160 and PLT 27. Dasatinib 100 mg daily was held.

Peripheral blood BCR/ABL PCR was 33% at diagnosis and 2% at 3 month check.

After a 2 week hold of dasatinib, platelets were uptrending to the 40s but then dropped again to <10. ANC has not shown any response.

Bone marrow biopsy/aspirate after 4 week dasatinib hold showed low cellularity (10-20%) without an expanded blast population by morphology or flow, however FISH shows 59.5% of cells are positive for BCR/ABL1 rearrangement and marrow RT PCR shows 25% BCR ABL transcripts.

PB BCR/ABL PCR now 4.9% after 7 week dasatinib hold. ANC remains <100 and requiring platelet transfusions 2-3x/week.

Seeking input regarding use of growth factor (GCSF and/or TPO agonists), role of HCT, and any other suggestions.

Thank you!