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!

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 109/L and platelet count > 50 x 109/L and then resume at a lower dose. Meanwhile, growth factor support can be used.

My best wishes for the boy's prompt recovery.