The Expression of shp-1 and SHP-2: A Novel Powerful Predictor of Major Molecular Response (MMR) Achievement in Chronic Myeloid Leukemia Gleevec-Treated Patients Enrolled into the TOPS Clinical Trial.
Authors: Esposito Nicola , Quarantelli Fabrizio , Luciano Luigia , Izzo Barbara , Peluso Anna Lucia , Picardi Marco , Branford Susan , White D.L. , Hughes Timothy , Radich Jerald , Soverini Simona , Iacobucci Ilaria , Saglio Giuseppe , Kalebic Thea , Thornquist Mark , Martinelli Giovanni , Pane Fabrizio 
Published: April 2020

Abstract
Imatinib (Ima) has dramatically improved the outcome of patients affected by chronic myeloid leukemia (CML) and became the standard care for patients with newly diagnosed CML in chronic phase (CP). In spite of treatment progresses and novel biological findings, Sokal index is still a dominant prognostic determinant of newly diagnosed CML patients also in the era of targeted therapies. In this study we investigated the predictive role of the levels of expression of two SHP-constitutive non receptor protein tyrosine phosphatase, the SHP-1 and SHP-2, in leukemia cells obtained from 48 newly diagnosed CML patients enrolled into the TOPS (Tyrosine kinase inhibitor Optimization and Selectivity) trial. TOPS is a prospective, open-label, randomized (2:1) Phase III trial that compared Ima 800mg/d to 400mg/d in CP-CML. The findings end point of the trial is the rate of major molecular response (MMR) indicated by several reports as a parameter that predict a benefit for progression free survival (PFS). Results indicate that the mRNA levels of both SHP1 and SHP2 assayed by QPCR in peripheral blood of newly diagnosed the patients and expressed as ratio to ABL, are significantly different between those patients who do and do not achieved MMR by 12 months (7.4 ± 3.8 vs 6.0 ± 3.2, p = 0.017 for SHP1/Abl % and 0.19 ± 0.15 vs 0.10 ± 0.12, p = 0.017 for SHP2/ABL%). There is not statistical evidence that patients who achieved MMR earlier than 12 months i.e. at 6 and 9 months, have different baseline levels of SHP1 or SHP2, however the data are suggestive of a difference which might become statistically significant with a larger sample size. Complete cytogenetic response, CCyR, was a secondary end point of the TOPS study, overall, 65% have achieved CCyR by 6 months, and 85% by 12 months, and although not statistically different, results indicate that both SHP1 and SHP2 levels tended to be higher in patients who obtained CCyR, and the our further study with a larger sample size will show if the differences might become significant. .SHP1/ABL % and SHP2/ABL % are weakly correlated each other in the patients, therefore each independently acts as predictor of MMR at 12 months and logistic regression indicated that the combination increases their prognostic value for predicting MMR in the first 12 months and using logistic regression, Sokal score does not add any discriminating power to either of those markers (either alone or in combination). In conclusion, our results indicate, that the levels of expression of SHP1 and SHP2 are useful predictors of MMR in newly diagnosed CP-CML patients. These data confirm our prior findings from “in vitro” studies, which investigated the role of SHP1 and SHP2 phosphatases in mechanisms which regulate Imatinib sensitivity.