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Unique Molecular Subtypes within BCR::ABL1-Postive ALL Show Prognostic Relevance

February 20, 2024

March 2024

Khylia Marshall

Khylia Marshall is a freelance journalist based in Tucson, Arizona.

Researchers have developed a predictive model for systematically subclassifying BCR::ABL1-positive acute lymphoblastic leukemia (ALL) into four unique and distinct biologic and clinically relevant entities, according to a study published in Blood.

There are currently two distinct diagnostic entities within BCR::ABL1-positive ALL: lymphoid only, in which the driver gene fusion BCR::ABL1 is observed only in lymphatic precursors, and multilineage, where BCR::ABL1 is found in other hematopoietic lineages similar to chronic myeloid leukemia. Diagnostic standards for this classification are not yet established.

Lorenz Bastian, MD, of University Medical Center Schleswig-Holstein in Kiel, Germany, and colleagues analyzed molecular subtypes in BCR::ABL1-positive ALL to better understand the biology and clinical phenotypes of the disease and to achieve more precise classification.

The study included 327 patients ages 2-84 (median age = 46 years) with BCR::ABL1-positive ALL — the largest integrative dataset of this entity currently available. Researchers analyzed samples with transcriptomic profiling, genomic profiling, and fluorescence in situ hybridization analysis of hematopoietic populations classified using fluorescence-activated cell sorting, ultimately evaluating the clinical outcomes of 98 adult patients.

Using an unsupervised analysis of this aggregated dataset, researchers confirmed two main clusters that exhibited clearly distinctive gene expression profiles. Analysis showed BCR::ABL1 in 28% to 99% of myeloid cells in 18 of 18 samples from the cohort termed “multilineage,” while BCR::ABL1 showed exclusively in lymphoid precursors or mature B cells in 13 of 16 (81.25%) samples from the cluster termed “lymphoid” (p<0.001).

Additionally, each of these two main clusters harbored two subclusters on the gene expression level.

To understand the underlying biologic differences between these subclusters, researchers analyzed genomic profiles of 149 cases. They found that each subcluster showed a distinct pattern of genomic aberrations: the two BCR::ABL1 multilineage subclusters were enriched either for deletions in HBS1-like translational GTPase (delHBS1L; p=0.001) or monosomy 7 (del7; p<0.001). One lymphoid cluster was enriched for homozygous deletions in IKZF1 (IKZF1; p<0.001), whereas the other one was enriched for homozygous CDKN2A/B deletions, PAX5 deletions, and hyperdiploid karyotypes (CDKN2A/PAX5; p<0.001 for all comparisons).

Moreover, these BCR::ABL1 cluster definitions represent distinct clinical profiles. For example, researchers found that white blood cell counts at diagnosis differed between the BCR::ABL1 clusters (highest in delHBS1L and CDKN2A/PAX5), there was a predominance of the CDKN2A/PAX5 subcluster in pediatric patients, and there was an increase in del7 cases in elderly patients who were more frequently classified as multilineage.

Researchers analyzed the clinical implications of these subtypes on a patient cohort (n=98) homogenously treated with imatinib combined with adapted chemotherapy and allogeneic hematopoietic cell transplant in first complete remission. Both multilineage and lymphoid cluster patients achieved comparable three-year disease-free survival (DFS) rates (DFS=70% vs. 61%, respectively; p=0.530). However, patients in the IKZF1-/- enriched subcluster experienced worse DFS (57%), while hyperdiploid cases showed an excellent DFS (100%), establishing the prognostic relevance of the newly identified BCR::ABL1 ALL subclusters.

Researchers cite the specific treatment approach as a limitation to the prognostic value of their findings. Moving forward, they hope to verify the prognostic relevance of genomic markers in other treatment strategies.

“The most important direction for future research is how immunotherapies are doing in the context of these subtypes,” study author Claudia Baldus, MD, also of University Medical Center Schleswig-Holstein, said. “With blinatumomab moving to frontline therapies and remarkable results achieved even with blinatumomab/tyrosine kinase inhibitor combinations alone, it will be important to learn how BCR::ABL1 multilineage cases do with a therapy directed to the CD19-positive lymphoid compartment. I think it will be very important to systematically identify BCR::ABL1 ALL subtypes in ongoing trials to learn how to make the best use of the current therapeutic armamentarium of lineage-specific and lineage-independent strategies. To facilitate this development, we have trained ALLCatchR, our freely available tool for subtype allocation in ALL, to robustly identify the new BCR::ABL1 ALL clusters.”

Meanwhile, Dr. Bastian said hematologists should “obtain transcriptome profiles for any patients [with ALL] to enable subtype allocations for specific diagnosis according to current disease classification and to guide critical decisions while we learn how different treatment strategies impact outcomes of these different subtypes.”

Any conflict of interest declared by the authors can be found in the original article.

Reference

Bastian L, Beder T, Barz MJ, et al. Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL. [published online ahead of print, 2023 Dec 28]. Blood. doi: 10.1182/blood.2023021752.

 

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