The outcome of adult patients with acute lymphoblastic leukemia (ALL) dramatically improved over the last decade, due to the use of intensive, pediatric-like regimens also in the adult population and also because of the always more refined understanding of the molecular lesions underlying ALL development. On top of this, minimal residual disease (MRD), by means of Immunoglobulins/TCR (IG/TR) markers, is considered the most important prognostic factor for patients¿ stratification and treatment intensification.
The Ph-like subgroup ¿ displaying a transcriptional profile similar to that of Ph+ ALL but lacking the BCR/ABL1 transcript and instead having a number of fusion genes variable from case to case- represent a challenge: 1) since there is no gold standard tool for its recognition; 2) the outcome of these patients, despite treatment intensification, is still dismal. In the trial GIMEMA LAL2317, designed for newly diagnosed B-lineage Ph- ALL, patients received an intensive chemotherapy regimen and 2 cycles of blinatumomab, a bispecific monoclonal antibody, which has proven extremely effective in the setting of relapsed/ refractory cases as well as in patients who remain MRD+ after chemotherapy. While the overall preliminary results of the trial are extremely promising, Ph-like ALL cases, despite the fact that also achieved MRD negativity by IG/TR, there was a significantly higher incidence of overt hematologic relapse, suggesting that in this setting MRD evaluation by IG/TR is not a reliable tool and other markers are urgently needed.
Thus, in the present project, we aim at evaluating MRD by using digital droplet PCR (ddPCR)- a 3rd-generation and more sensitive PCR approach- using, instead of IG/TR markers, patient-specific fusion genes, that will be evaluated at diagnosis and during follow-up in order to rule out if this approach can reveal cases who remain MRD+ positive and therefore need further intensification, based on the use of a tyrosin kinase inhibitor.
The present project represents an important step forward for a further comprehension of Ph-like ALL cases, which nowadays represent the most relevant unmet need within ALL cases. In fact, as already mentioned, these patients are characterized by a highly heterogeneous genomic scenario, which is variable from patient to patient and the overall outcome of these patients is far inferior from the other ALL cases.
Indeed, in an era of great improvement in the management of adult ALL cases, due to the introduction of intensive treatment, MRD-driven strategies and further implementation of therapeutic backbone with immunotherapeutic compounds, we are still facing with the fact that these patients have a suboptimal response.
First of all, the extensive genomic characterization that has been partly already carried out, is allowing to clarify that within Ph-like ALL cases there are at least two distinct subsets: the first, devoid of recognizable fusion genes, appears to display a better outcome- similar to that of non Ph-like ALL cases, and the second, in which targeted RNA-sequencing permitted to define a specific gene rearrangement, which again is variable from to case, whose outcome is particularly dismal.
Second, rather unexpectedly and disappointingly, the use of blinatumomab, which is nowadays considered as one of the most promising drugs, not only did not abrogate the unfavorable outcome of these cases overall, but somehow ¿masked¿ the disease, since MRD proved negative after its administration. Thus, not only there is an advance in the field because we were able to understand that an immuno-chemotherapeutic strategy is not sufficient to overcome the negative prognostic impact of the Ph-like signature, but we could also better comprehend that we need other markers, represented by fusion genes that are identified at diagnosis and vary from case to case, to precisely follow these patients.
The set-up of a patient specific ddPCR assay, which represents the core of the project, might represent an important step forward for defining the persistence of disease, and therefore will allow a more refined uinderstanding of the mechanisms of leukemia escape and might orient, in a biologically-driven fashion, therapeutic intervention. We chose to use ddPCR since this technique appears slightly more sensitive than conventional quantitative PCR and does not require neither calibration curve nor diagnostic material, which can sometime be troublesome, since it is often lacking during subsequent follow-ups (due to use with Q-PCR).
Ultimately, but not least important, the results derived from the current proposal, are pivotal to design an ad hoc therapeutic strategy, specifically designed for Ph-like ALL patients, which contemplates the use of a chemotherapeutic backbone combined with immunotherapy and targeted treatment: as for this last issue, we deem that ponatinib - a third generation pan tyrosin kinase inhibitor ¿ might be the ideal compound since it has a wide spectrum of targets. Indeed, we previously showed its activity both in vitro and in vivo (Lunghi et al, 2021).
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