PB1943 SECOND GENERATION TKIS GUARANTEES A FASTER, DEEPER AND LONGER LASTING MOLECULAR RESPONSE COMPARED TO IMATINIB. AN ANALYSIS OF REAL LIFE
Authors: Luciano L. , Annunziata M. , Palmieri R. , Rivellini F. , Maglione V. , Zacheo I. , Bellisario F. , Pane F. 
Published: June 2019

Background:

The achievement of fast, deep and sustained molecular response(MR4 – MR4,5) in chronic myeloid leukemia patients treated with TKIs, ensure not only the stability of the disease with better outcome, improved EFS, PFS and OS but also the possibility to achieve the treatment discontinuation (TFR) with the maintenance of the response.

The two main clinical trials comparing second generation inhibitors in the first line with Imatinib (Nilotinib in ENESTnd and Dasatinib in DASISION) showed that second‐generation inhibitors obtain a more rapid and deeper molecular response than Imatinib. However, there is not in the literature a direct comparison between the three first line inhibitors in terms of speed and depth of response and maintenance of it.

Aims:

The aim of the study was to evaluate the differences between the three inhibitors, Imatinib, Nilotinib and Dasatinib, in CML patients front line, in obtaining the molecular response, both in terms of speed and depth and of maintenance of the response.

Methods:

We evaluated the timing and depth of the molecular response and its maintenance in 277 CML patients treated frontline with Imatinib (IMA), Nilotinib (NIL) or Dasatinib (DAS) in a real life cohort from 4 Italian hematology units in Campania. The molecular response was assessed according to the international standard procedures suggested by the European Leukemia Network (ELN).

Results:

The median age of patients was 59y (range 15‐91), 153 were male; 109 patient were treated with IMA, 98 with NIL and 68 with DAS.

At three months, 45 pts reached Early Molecular Response (EMR)as by ELN recommendations (BCR/ABL< = 10%), 17 pts with IMA, 22 pts with NIL and 6 pts with DAS.The major molecular response (MMR) at one year was documented in 121 pts: 36 with IMA, 53 with NIL, 32 with DAS (Fig 1).

A sustained deep molecular response was obtained in 39, 61 and 38% of Imatinib, Nilotinib and Dasatinib treated patients, respectively and the differences were statistically significant (chi‐square test, p < 0.001). Time to deep molecular response was 35, 18 and 23 months in Imatinib, Nilotinib and Dasatinib group, respectively with a strong statistically significant difference between first and second generation TKIs (Umpaired T‐test IMA vs NIL: p < 0.0001; IMA vs DAS: p < 0.02) and no statistical difference between DAS and NIL(p = 0.178).

14 patients were not evaluable: 2 for the presence of atypical transcript, 4 pts were lost at follow‐up, no data was available for 2 patients and 6 patients had short follow‐up.

In the cohort of IMA, 8patients were primary resistant, 8patients showed secondary resistance, most at 12 months.

In NIL group 6pts showed resistance, only one secondary; in DAS group 7 were resistant, 3 secondary resistance.

Summary/Conclusion:

Conclusion

Our data, comparing all 3 TKIs in front line, show that the second generation TKIs guarantees a faster and deeper molecular response compared to Imatinib, especially Nilotinib showing a statistically significant major number of deep and sustained molecular responses, while Dasatinib, despite inducing faster and deeper molecular responses, causes more discontinuations due to side effects (pleural effusion).

The faster and deeper molecular response with second generation TKI in the treatment of CML, allowing patients to achieve the “safe haven” of deep molecular response which guarantees the stability of the disease and the possibility of TFR over time.