11 year old girl, diagnosed with CML in lymphoid blast crisis (BCP ALL)
Presenting white cell count: >50,000/cumm
CNS1 at diagnosis
p190 transcript (e1a3) - so tracking not possible by RQPCR.
Initially treated with pediatric ALL protocol (ICICLE ALL 14) with Imatinib: Date of start of treatment: 17 July 2019
End of Induction Flow MRD: 0.074%
End of Consolidation flow MRD: 0.0004%
Nested PCR positive for e1a3
Completed ALL Maintenance: April 2022
Not transplanted due to lack of donor
Doing well on Imatinib since then

Feb 2026: Transition of care to adult hem-onc team
Current age: 19 years, asymptomatic, no splenomegaly, however, counts increasing (WBC: 13000/cumm).
Nested PCR positive for e1a3
Donors: 1 haplo matched sibling and parents available. No MUD available
TKI changed to dasatinib

Questions to the experts:
1. As this is a patient with CML-BC: should we transplant this child now, after a period of 8 years (Disease in apparent CP?).  
2. Is there a way to monitor this uncommon transcript e1a3 ? Can a RQPCR be set up in any way?
3. Any role of NGS at this point of time?
4. Choice of TKI in this case?


With regards,
Dr. Shouriyo Ghosh, India
 

Although the patient is currently in chronic phase, this is a second chronic phase, and there is likely a high risk of relapse of blast phase CML. As haplo donors are available, I would be considering allogeneic stem cell transplant now before disease progression occurs. If the patient is responding to dasatinib, I would continue on this as it has penetration of the blood brain barrier. If patient is intolerant, or response is lost to dasatinib, then I would switch to ponatinib (also has some CNS penetration) after doing a BCR::ABL1 kinase domain mutation screen. On recovery of counts post-transplant, I would re-start the TKI the patient was responding to pre-transplant and continue this for 2-3 years if possible.
Regarding qRT-PCR monitoring, it would be worth discussing with your lab to see if they can set up a patient-specific quantitative PCR assay. This is possible from some patients with atypical transcripts. I don't think there is a role for NGS as this won't change your management if planning to proceed to transplant anyway.

Best wishes
Mhairi

I am sorry to hear about the challenging case. It looks like the nested PCR positive for e1a3 has not changed. Have you done flow cytometry this time? can you follow the clone by NGS MRD such as ClonoSEQ? I am not sure about the meaning of increasing counts without them. You have haplo donors now - were the haplo-matched siblings and parents unavailable previously? If that is a real increase of blasts, I would transplant her at this point. If not, I may continue dasatinib.

Thanks.

Nobuko

This is a rare adolescent CML case because i) relapse after initial presentation as CML-BP occurred rather late and because ii) relapse presented as CML-CP. Nevertheless, I have observed such cases before [published as EBMT abstract: Claviez A, Klingebiel T, Peters C, Kalwak K, Kabisch H, Viehmann S, Harbot, J, Schrappe M, Suttorp M: Outcome of transplantation in six children presenting initially as Ph+ ALL and with first relapse as Ph+ CML (Abstract). Bone Marrow Transplant 27 (Suppl. 1): S145 (2001)].

Given the young age of the patient and the background of an inital presentation as CML-BP there is now is a clear indication for SCT (Answer to question 1). In addition, the TKI treatment should be restarted after SCT for another 2 – 3 years with 3-monthly monitoring.

To bridge the time until the SCT from the haploidentical sibling as donor will be organized, I recommend to continue dasatinib treatment. In case of no response (no decline of leukocytosis), ponatinib would be the alternative (Answer to question 4).

For monitoring the uncommon e1a3 transcript, I would talk to the scientists in the lab and ask them if they could establish a quant.-RT-PCR assay for this special case. Alternatively, the chromosomal fusion point on the DNA-level could be identified and the treatment efficcacy monitored with a DNA probe providing high sensitivity [Krumbholz M, Goerlitz K, Albert C, Lawlor J, Suttorp M, Metzler M. Large amplicon droplet digital PCR for DNA-based monitoring of pediatric chronic myeloid leukaemia. J Cell Mol Med. 2019 Aug;23(8):4955-4961.] As a rather insensitive method, interphase FISH (~1-2% sensitivity) from periheral blood is also possible (Answer to question 2).

NGS in CML has much improved our understanding of its genetic complexity (additional mutations associated with disease progression, therapy resistance, clonal evolution, identification of rare BCR::ABL1 fusion variants and cryptic rearrangements). For MRD monitoring, NGS will detect evolving resistance patterns, thus allowing optimization of targeted therapeutic strategies. However, data interpretation, not fully established standardization, and cost constraints would prevent me from using this method right now in the case under discussion (Answer to quesion 3). [For a more detailed review see; Sutanto H, Pratiwi L, Romadhon PZ, Bintoro SUY. Advancing chronic myeloid leukemia research with next-generation sequencing: potential benefits, limitations, and future clinical integration. Hum Genet. 2025 May;144(5):481-503. doi: 10.1007/s00439-025-02745-x. Epub 2025 Apr 21. PMID: 40257486].

All my best wishes for your patient!

Meinolf

Transplant ASAP. Unpredictable remission duration but definitely not cured. 8 years would be a dream. Use best available haplo. Monitoring would require the creation of patient specific primers.

That the patient did well for such a long period is remarkable.

The e1a2/p190 BCR-ABL1 transcript is a rare, molecular variant (found in 1–2% of cases) of Chronic Myeloid Leukemia (CML) that results in a 190 kDa protein, commonly associated with more aggressive, kinase-inhibitor-resistant disease and a higher rate of transformation to blast crisis.

It is distinct from the more common p210 (e13a2/e14a2) variant in several aspects.

Clinical Presentation: typically presents with peripheral blood monocytosis, fewer signs of splenomegaly, and can resemble intermediate features between CML and chronic myelomonocytic leukemia (CMML).

Prognosis: Associated with poorer responses to standard tyrosine kinase inhibitors (TKIs), requiring closer monitoring or alternative therapies like ponatinib.

Genetics: Occurs due to a breakpoint in the BCR gene, leading to the e1a2 exon fusion.

It is more typically found in Ph+ Acute Lymphoblastic Leukemia (ALL) rather than CML.

Treatment: While TKI resistance is common, some cases show response to second-generation TKIs (e.g., dasatinib, nilotinib).

One can monitor it with droplet digital pcr or multiplex PCR.

GeneXpert may miss it.

ENL has not yet standardised the test or the clinical and lab milestones for this rare mutation.