Clinical Case Discussion Forum

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!

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.

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

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.

Normal hemopoiesis has not recovered for whatever reason and what does recover here is clonal. All the TKIs are good at shutting down the CML clonal hemopoiesis and switching will not change things. Persistent cytopenias is one of the very few indications for stem cell allografting and as I pointed out in a very recent commentary in Am J Hem, nothing will be gained by delaying and the risk of cytopenia related problems can only get worse. This is a young man and should have a good transplant outcome. I agree with Tim, but would not delay.

Thank you Prof for the comprehensive analysis of the situation. I am from Uganda and we face such challenges. However, I wish to be enlightened on why the first line treatment was dasatinib and at a high dose. I think we have not identified any ABL1 mutations in this young patient but what would be the role of other lines of treatment? I am asking this because in low income settings access to Allotransplants is not possible.

Henry

Clear indication for an allogeneic stem cell transplantation.
Deficient underlying Ph neg hematopoiesis.

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?

Dear Colleagues,

I don't have enough information to make a decision. To clarify the cause of cytopenia, it is necessary to perform a trepanobiopsy. In the era before TKI, myelofibrosis in the bone marrow was not rare (mainly in patients with hyperthrombocytosis).

My suggestions: if this patient is in a low-risk group, I would not rush to allo BMT. It may be recommended to prescribe dasatinib at a dose of 50 mg per day and eltrombopag 50 mg x2 times a day (increased dose). Evaluate the results of therapy after 3 and 6 months. When the platelet count has stabilized, eltrombopag is discontinued and increase the dose of dasatinib to 100 mg.

In a case of a high-risk patient with myelofibrosis, allo-BMT may be the optimal solution.

Kind regards - Professor Anna Turkina

Marrow is empty and biopsy has been done. Although CML seems to have responded to DAS, normal hemopoiesis has not recovered.

This child is pancytopenic and at risk. G-CSF could be tried for a week or so to see if there is any response and this will give you an idea if there is any functioning reserve. I would not wait 3 months to see if platelets respond to eltrombopeg.

If no response to the G-CSF, I would not wait around for a problem. A lower dose of DAS or a drug switch will not allow recovery of what is not there. Proceed with an allograft. Waiting just increases the risk of infection, bleeding and/or platelet refractoriness developing. I continue to stand by the strategy that if SCT is on the table, waiting does not improve things and may make them worse

Hi, i agree with others that this is an ominous combination of severe myelosuppression coupled with response albeit limited. I do not see ABL mutation testing, this may be informative for any therapy in the short or long term; it is intriguing there was stability followed by severe cytopenias, suggesting expansion of different clones. Historically transformation risk is high in these cases of severe myelosuppression and limited response, especially as therapy is difficult if at all and dose intensity drops. Growth factors may be tried to stabilize/bridge. Allografting seems the right path especially as disease burden is rising.

Thank you for your response.

Patient fortunately has good donor options and is a good candidate for transplant, so we are moving forward with allo BMT.

We trialed GCSF 5 mcg/kg for 2 weeks with no response (ANC remained 40-60 throughout this time) so have now stopped it.

I repeated a bone marrow 2 weeks ago which showed cellularity <10%. His BCR ABL PCR is interestingly down quite a bit- only 5.474% (major breakpoint e13a2, with 0.011% minor breakpoint e1a2) compared to 24% (0.020% minor breakpoint) in his marrow back in May. Dasatinib has been on hold since early April.

Myeloid NGS panel and BCR ABL mutation analysis were sent from most recent marrow, and are still pending.

My one question at this time is whether to start asciminib to try to get any more disease control prior to BMT, or to keep him off TKI so as to not further suppress any chance of possible delayed spontaneous recovery.

Thank you!

Thank you so much for your thoughts and recommendations.

We are moving forward with allo HCT as soon as possible. Trialed GCSF for 14 days with no response. Marrow still <10% cellularity, predominantly erythroid precursors. BCR ABL PCR down to 5% without any other intervention since last marrow 1 month prior (off TKI >2 months now).

Any thoughts on utility of starting asciminib to try to get as much disease control as possible prior to transplant? I see both pros and cons.

Hi there, I opted to start with dasatinib as first line TKI for this patient as he was an older teenager. Since dasatinib may be associated with faster and deeper molecular response than imatinib, I figured it may have a better chance at TFR later down the line. And dasatinib 100mg is standard FDA approved dosing (BSA 1.8)

Mild reticulin fibrosis (MF-1) without collagen fibrosis in both his diagnostic marrow and his most recent marrow. I have not been comfortable restarting any TKI at this point because of his persistent profound cytopenias (Plt <10, ANC <100 for 10+ weeks).