Acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising several molecularly defined subgroups. Among these, the BCR/ABL1-like (alias Philadelphia-like) subset has been recognized by gene expression profiling: it displays a transcriptional profile that resembles that of true BCR/ABL1-positive cases, contains activating tyrosine kinase lesions and JAK/STAT mutations, and is associated with a poor outcome. The genomic background varies from case to case, thus making the design of a single diagnostic assay difficult. Our group (Chiaretti et al, 2018) recently generated a tool, named BCR/ABL1-like predictor, for the identification of these cases at diagnosis. This tool is economic and quick. If applied at diagnosis, it may prompt the design of novel treatment schemes, including the upfront use of a tyrosine kinase inhibitor (TKI), aimed at improving the outcome of adult BCR/ABL1-like ALL patients.
In this study, we will apply the BCR/ABL1-like predictor to all newly-diagnosed cases enrolled in the front-line GIMEMA trial LAL1913 - based on a pediatric-inspired chemotherapy scheme and further intensified according to the levels of minimal residual disease (MRD) - as well as in the forthcoming trial LAL2317, based on the same backbone but implemented with blinatumomab, a bispecific monoclonal antibody.
Besides confirming the incidence, clinical features and outcome of this subset, the project aims at refining the molecular landscape of BCR/ABL1-like ALL cases by using RNA-sequencing, mutational screening and copy number aberrations (CNA) analysis to gain a deeper insight in the underlying lesions, with the final goal of further stratifying this group of patients from a molecular and clinical standpoint. It is likely that this subgroup includes cases with a different prognostic likelihood. Finally, we will further confirm the reproducibility of this approach through international collaborations based on sample sharing and sample retesting.
The current project will improve the knowledge on adult ALL in general, and more in detail on BCR/ABL1-like cases, which represent, in our report, as much as 30% of B-ALL cases without major molecular aberrations and are an unmet clinical need, given the poor outcome reported in all studies. Indeed, the description of this subgroup dates back to first years of 2000, but it is still incomplete and the identification of these cases is laborious and not standardized.
- We will apply the BCR/ABL1-like predictor to all adult ALL cases enrolled in two consecutive italian GIMEMA trials, based on a pediatric-derived and MRD-oriented strategy (LAL1913 and LAL2317), the first having just closed to enrollement and the second one soon opening to patients recruitment. Overall, these two trials will guarantee the availability of about 250 patients, of which 75 are predicted to be BCR/ABL1-like: therefore, we will be able to reliably describe the clinical features of these patients and their outcome. If deemed necessary, also non-BCR/ABL1-like will be screened for the above mentioned techniques.
- Since both protocols are based on MRD stratification, we will also be able to correlate the BCR/ABL1-like profile with MRD levels. In this respect in fact, it is not yet established the interplay between MRD and the BCR/ABL1-like profile and it is not clear if the prognostic impact of the BCR/ABL1-like profile might be overcome by MRD negativity or viceversa.
- Furthermore, this project represents the ideal setting to elucidate if the use of immunochemotherapeutic regimens (the monoclonal bispecific antibody blinatumomab will be administered in the GIMEMA LAL2317) can overcome the poor prognostic impact of the BCR/ABL1-like profile.
- The in-depth genetic characterization (i.e. RNA-sequencing, mutational screening and MLPA) of BCR/ABL1-like cases will increase the current knowledge on the molecular background of these patients and will most likely identify prognostically and therapeutically relevant subgroups: to this end, the identification of actionable lesions will prompt the design of targeted approaches. Indeed, our group is designing a trial based on the upfront use of ponatinib, a third generation pan-TKI, which has shown in vitro efficacy, regardless of the underlying lesions. If lesions refractory to this inhibitor will be identified, other targeted strategies will be investigated.
- Finally, the reproducibility of the BCR/ABL1-like predictor, will be tested thanks to external collaborations, established all over Europe through the network of EWALL. This will guarantee the creation of a standardized assay for the prompt identification of this difficult subset.
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