CML-like biology: BCR::ABL1 and beyond

In this issue of Haematologica, van Outersterp and colleagues report the case of a child first diagnosed with B-cell precursor acute lymphoblastic leukemia (ALL) at the age of two, who relapsed three years later with different immunoglobulin (IG) and T-cell receptor (TR) rearrangements. At relapse, an ABL-class fusion, CCDC88C::PDGFRB, was identified as the primary genetic lesion that could be successfully retrospectively identified as primary aberration also in the initial diagnosis.¹

Although the retrospective nature of the study and limited availability of material meant that the depth of analysis was limited, the authors provide convincing evidence that the primary aberration (here an ABL-class fusion) was present within a broader hematopoietic clone extending beyond the lymphoid lineage. It was only after the acquisition of additional, secondary lesions (genomic losses involving, e.g., PDE4B, RUNX1, TOX) that differed between diagnosis and recurrence, that a fully leukemic ALL clone emerged. The biology and clonal architecture, therefore, resemble those of the recently recognised subtype of ALL assigned as chronic myeloid leukemia like (CML-like) disease, also referred to as BCR::ABL1-positive B-ALL with multilineage involvement.^2,3 The patient described is part of a previously reported cohort of 22 patients harboring non-BCR::ABL1 ABL-class fusions,⁴ and another study presented 21 such patients.⁵ Importantly, this child was the only one across both series to show discordance between quantitative monitoring of genomic levels of the ABL-class fusion and IG/TR rearrangements during therapy. This suggests that such cases are relatively rare among non-BCR::ABL1 ABL-class positive leukemias: 1 in 43 (2.3%) compared with up to one-third of BCR::ABL1-positive ALL.³ Nonetheless, it clearly confirms that the phenomenon can, indeed, occur outside the context of BCR::ABL1. This case report raises several thought-provoking questions. I will highlight just two of them here.

The first relates to molecular monitoring of minimal residual disease (MRD) in ALL and the choice of clonal markers. In routine practice, MRD assessment relies primarily on IG/ TR gene rearrangements. This approach is well standardized, validated and incorporated into virtually all treatment protocols. However, owing to subclonality, ongoing IG/TR rearrangements during treatment, or, as in this case, specific aspects of disease biology, these rearrangements do not necessarily capture the entire malignant or aberrant clone. Previous work has shown that a ‘pre-leukemic clone’, marked by the presence of a primary aberration but lacking the additional mutations required for full transformation, may persist even after eradication of clinically overt leukemia.^6-8 Such clones can serve as a reservoir of potentially dangerous cells, capable of giving rise to recurrence following a new ‘second hit’, though such recurrence may not represent a classical relapse. This biology has been described in ETV6::RUNX1-positive ALL^{6 ,7} and in BCR::ABL1 CML-like ALL,⁸ and now appears to also extend to other ABL-class fusions.¹ Whether this phenomenon is more common in ALL remains uncertain, but comprehensive monitoring of both the primary genetic lesion and IG/TR rearrangements (or other clone-specific markers) seems to be a way to identify it. Whereas, until recently, tracking primary aberrations at the DNA level was technically challenging, advances in and the increasing accessibility of sequencing approaches, including whole-genome sequencing, are rapidly changing this landscape; this can already be seen, as, for example, in acute myeloid leukemia.⁹

A second important issue is whether some of the pressing clinical questions we have recently been facing in BCR::ABL1-positive ALL (particularly in CML-like cases) may also be relevant to other ABL-class fusions. One such dilemma arises at the end of front-line therapy: how should we proceed when markers of the fully transformed leukemic clone (typically patient-specific IG/TR rearrangements, sometimes others) have long been negative, but the primary aberration (BCR::ABL1 or another ABL-class fusion) remains detectable?^8,10 Thoughts on this topic are hampered by the fact that, particularly historically, such patients were not further monitored, and even today, their follow-up after completion of the protocol is definitely not routine. Therefore, there is still a lack of extensive data. We are trying to fill these gaps by putting together information on individual experiences and through active international co-operation.

Figure 1.The origin of ‘chronic myeloid leukemia-like’ leukemia (initiated by BCR::ABL1 or another ABL-class fusion) and two different types of disease recurrence. BCP-ALL: B-cell precursor acute lymphoblastic leukemia.

However, broadly speaking, three strategies can be considered: i) a ‘watch and wait’ approach, with regular MRD monitoring but no active intervention; ii) continuation of targeted therapy, usually with tyrosine kinase inhibitors (TKI), possibly in combination with immunotherapy; or iii) identification of a donor and proceeding to allogeneic transplantation in the first remission.

Each option has advantages and drawbacks. On the one hand, there is the risk of recurrence, whether as a classical relapse of the original clone or as a ‘new’ leukemia arising from a reservoir of pre-leukemic cells, as illustrated both here and in CML-like BCR::ABL1-positive cases.^1,8 On the other hand, long-term TKI therapy carries a non-negligible toxicity, particularly in children. Moreover, clinical experience (including this case) suggests that TKI alone rarely achieve a meaningful reduction or eradication of the pre-leukemic clone.^1,8,10 This is probably because, unlike fully transformed leukemic cells, these cells are not dependent on the aberrant kinase for survival, and thus are relatively unaffected by its pharmacological inhibition at the protein level. Whether the continued TKI treatment can, at least, decrease the risk of clinical recurrence remains to be established. Targeted immunotherapies are another possibility, but those directed against lymphoid markers (e.g., anti-CD19, anti-CD22) are of limited efficacy here, since in CML-like leukemias at least part of the aberrant clone resides outside the lymphoid lineage. Transplantation, therefore, probably remains the only option that can offer the possibility of a complete cure. Yet recommending it in a patient in morphological remission, often without clinical signs of disease, and who would appear entirely healthy if the primary aberration were not being monitored, is far from a straightforward and easy decision. Should recurrence occur, however, the scenario changes markedly, and a second remission still offers a reasonable chance of successful transplantation.

We have already offered some recommendations,⁸ but, as mentioned above, robust conclusions will require collection and integration of more cases, both with BCR::ABL1 and with other ABL-class fusions. Efforts are under way to organize and co-ordinate this process, and, given the relative rarity of these cases, close collaboration with colleagues across centers and countries is essential. Only then will we be able to build sufficiently robust, evidence-based guidance for tackling these challenging situations.

Footnotes

• Received October 6, 2025
• Accepted October 24, 2025

Correspondence

J. Zuna jan.zuna@lfmotol.cuni.cz

Disclosures

No conflicts of interest to disclose.

Funding

Co-funded by the EU and the State Budget of Czechia OP JAC, project SALVAGE, N. CZ.02.01.01/00/22_008/0004644, and by the Czech Health Research Council NW25-03-00276.