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Ph-like ALL correlates with MRD+ and outcome
parameters and genetic prognostic markers were taken into account the Ph-like profile proved the only risk factor for MRD positivity at TP2. Thus, considering both response to induction treatment and MRD monitoring, the Ph-like status, if identified early, permits not only to recognize patients who are likely to be refractory to induc- tion treatment, but also to identify - within cases who achieve a CR - those who are likely to remain MRD-posi- tive. This strong association may allow to anticipate ther- apeutic changes.
To our knowledge, this is the first study that analyzes the interaction between the Ph-like status and MRD - assessed by quantitative PCR of the IG and TR gene rearrangements - in a broad cohort of uniformly and prospectively treated adult ALL patients within a clinical trial. Similar results were provided by Herold and col- leagues6 who found that Ph-like patients were less likely to achieve a MRD-negative status in a small cohort of 31 patients with overlapping MRD and Ph-like status infor- mation. In the pediatric setting, contradicting results have been reported.14,16
Furthermore, the comparison of survival curves high- lighted that Ph-like patients experienced a significantly worse EFS at 24 months compared to that of non-Ph-like cases (33.5% and 66.2%, respectively). Along the same line, also in cases achieving a CR, the Ph-like profile had a negative prognostic impact, as shown by the worse DFS of Ph-like patients. Although limited by the small sample size, our study demonstrates that transplant is beneficial in these cases and should be pursued at the earliest oppor- tunity, as shown by the high rate of relapses within non- transplanted Ph-like patients (4 of 5 MRD positive patients relapsed).
Lastly, in all outcome parameters evaluated - CR achievement, MRD at TP2 and EFS - the Ph-like status emerged as an independent prognostic marker.
In addition to confirming the inferior outcome of Ph-like ALL patients, these data indicate that the differences between Ph-like and non-Ph-like cases are not abolished by pediatric-like intensive therapeutic schemes, in agree- ment with the results of the MDACC group.18 Based on the MRD findings hereby reported, this is primarily con- tributed to the significantly lower rates of complete molecular responses observed in Ph-like patients.
In light of the poor outcome of Ph-like ALL and of the possibility of using targeted approaches,30 different clinical trials specifically designed for Ph+ ALL and Ph-like ALL cases are testing the efficacy of dasatinib (clinicaltrials gov. Identifier: 02420717, 02883049, 03564470 and 02143414) or of dasatinib in combination with blinatumomab (clini- caltrials gov. Identifier: SWOG-S1318 and NCT02143414). Other studies are investigating the impact of blinatu- momab in combination with chemotherapy in Ph-nega- tive B-lineage ALL (GIMEMA LAL2317, clinicaltrials gov. Identifier: 03367299 and 02003222). In these latter studies, it is investigated if the addition of blinatumomab can
increase the rates of CR and MRD-negativity in Ph-like patients, as already observed in Ph+ ALL.32 In support of the fact that Ph-like patients may benefit from targeted treatment, a recent study from Tanasi and colleagues has reported that the introduction of TKI front-line was asso- ciated with a 3-years OS of 77%.31 Other compounds, such as ruxolitinib (clinicaltrials gov. Identifier: 02420717, 03571321 and 02723994) and the histone deacetylase inhibitor chidamide (clinicaltrials gov. Identifier: 03564470) are under investigation.
Taken together, the results of this study carried out on adult B-NEG ALL cases enrolled in the front-line GIMEMA LAL1913 clinical protocol confirm that the BCR/ABL1-like predictor7 is a valid tool to rapidly recog- nize Ph-like cases that account for about 30% of adult B-NEG ALL. In addition, we could show that also in a pediatric-oriented and MRD-driven clinical trial Ph-like patients have a lower probability of achieving a CR, are more likely to remain MRD-positive and have a signifi- cantly shorter EFS. The Ph-like profile is an independent risk factor for CR failure and MRD-persistence, thus fur- ther underlying the need that Ph-like cases - a primary unmet clinical need in ALL - are rapidly recognized at diagnosis in order to refine the risk stratification of Ph- negative ALL and optimize patients’ management. Further investigations are currently ongoing to unravel if within Ph-like ALL there are subgroups of patients with a differ- ent outcome likelihood.
Disclosures
No conflicts of interest to disclose.
Contributions
SC designed research, analyzed data, provided clinical sam- ples and clinical data,and wrote the manuscript; MM performed experiments, analyzed data and wrote the manuscript; AP per- formed statistical analyses; IDS, LC, AT, MC, LE, GAP, RLS, MCAL, MCP, VP, AS, OS, VA performed experiments; SC, FDR, PDF, CP, AC, RC, MC, NF, DM, CC, AV, provided sam- ples and clinical data; EC and PF contributed to protocol man- agement; AG and CM critically revised the manuscript; AR and RB designed the trial and critically revised the manuscript; RF designed the research and the trial, and critically revised the man- uscript.
Acknowledgments
The authors wish to thank Grazia Fazio and Chiara Palmi for support in TruSight Pancancer and MLPA experiments, Associazione Italiana per la Ricerca sul Cancro (AIRC) 5x1000, Special Program Metastases (21198), Milan (Italy) to RF; Finanziamento Medi Progetti Universitari 2015 to SC (Sapienza University of Rome); Bandi di Ateneo per la Ricerca (Sapienza University of Rome, RM11816436B712AF) to SC and PRIN 2017 (2017PPS2X4_002) to SC, CM, and RLS; Fondazione Cassa di Risparmio di Perugia (grant number 2018.0418.021) to RLS.
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