Efficacy of Nilotinib in EARLY Chronic PHASE CML Patients WHO Have Suboptimal Cytogenetic or Molecular Response to Imatinib. A Multicentric Retrospective Study
Authors: Luciano Luigia , Seneca Elisa , Annunziata Mario , Pezzullo Luca , Danise Paolo , Sessa Ursula , Palmieri Fausto , Iovine Mariolina , Vallone Roberto , Pane Fabrizio 
Published: October 2019

Abstract
Abstract 4454
The CML-CP suboptimal responders rappresent an eterogenous group of patients in which it is possible either to obtain an optimal renponse or to experiment a failure. The Clinical data of MDACC, Hammersmith Hospital and GIMEMA group showed that patients with suboptimal response at 6 and 12 months have worse long term outcomes than patients with optimal responses, particularly if the suboptimal response occurs early in the treatment, suggesting an advantage for pts with early major molecular response, expecially for event free survival and progression free survival. Moreover, recently, the German group has shown the benefit of early major molecular response on overall survival too. So earlier use of nilotinib or dasatinib in suboptimal CP CML may be beneficial in two potential ways:
by promoting an early response, thereby potentially improving prognosis; by avoiding the development of treatment resistance.
The clinical challenge in this setting would be to accurately identify patients who are likely to fail treatment with TKIs.
This retrospective analysis was designed to explore the efficacy of the early switch to Nilotinib in patients with suboptimal responses to imatinib (IM) according to ELN raccomandations.
In this multicentric retrospective study, 15 CML-CP patients with suboptimal response to IM within 24 months from diagnosis were evaluated: 4pts with a low, 3 with intermedied and 5 with high Sokal score. The best response to IM was CCyR for 6 pts, PCyR for one pt and Complete Hematological Response for 5 pts. As for suboptimal responses, 5 pts were defined in suboptimal cytogenetic response: 2 pts at 12 months and 2 pts at 6 months; 6pts were 18 months suboptimal molecular responders and 1 pt had a loss of CCyR at 12 months.
All patients were switched to Nilotinib 400 mg twice daily. Bone marrow was done at baseline in all pts and at 3,6,12 and 18 months in cytogenetic suboptimal pts, while the molecular analysis was performed on peripheral blood every three months in all other pts.
12 pts have been treated with Nilotinib for a median of 17,5 months (range 3–37), 9 patients for ≥ 12 months. Before switching to Nilotinib, pts were treated with IM 400 mg once daily apart for 2 patients who needed an adjustment dose to 300 mg and 600 mg for toxicity and suboptimal response, respectively.
Among 6 pts with suboptimal CyR, 4 obtained CCyR, 3 at 3 months and one at 6 months; 2 pts had any response at the milestones timepoints and they switched to another therapy. All pts with molecular suboptimal response obtained MMR at 3 months apart for one, who showed MMR at 12 months.
Nilotinib was well tolerated in all 12 pts; only one developed a moderate transaminase elevation. A brief drug intrerruption was sufficient to manage this adverse event.
Our data confirm that second generation TKIs give deeper and earlier responses also in second line treatment, garantendo optimal PFS and OS. In our serie infact, Nilotinib treatment results in high and relatively quick cytogenetic and molecular response rate in CML –CP-pts with suboptimal response to IM.
These results demonstrate that the early switch to Nilotinib could be raccomanded in suboptimal responders in order to improve the outcome of this kind of pts and strongly suggest the second generation TKI as first line therapy in CML patients. A larger patient population and a longer period of observation could allow to confirm these preliminary data.

Disclosures:
No relevant conflicts of interest to declare.