Page 104 - 2019_11 Resto del Mondo-web

S. Claudiani et al.
achieved MR3, five were in MR4, and seven in MR4.5. Of the 14 patients who lost MR4 but not MR3, none had lost CCyR at a median follow up of 39.2 months (range: 26- 89.3 months). At last follow up, five patients were in MR3, five in MR4, and four in MR4.5.
The response status at last follow up on TKI and treat- ment status at last follow up are summarized in Online Supplementary Figure S2.
Overall survival
The 5- and 10-year OS were 98.8% (95%CI: 98.7-98.9) and 96.8% (95%CI: 94.2-97.3), while CML-OS were 100% and 99.4% (95%CI: 98-99.8) (Figure 4A). The 5- year EFS after the first year in MR3 was 97.3% (95%CI: 95.2-98.5) (Figure 4B). Overall, 11 deaths were recorded at a median follow up from diagnosis of 122.5 months (range: 17.5-234 months). Of these, only two were direct- ly related to CML. Other causes of death included chronic obstructive pulmonary disease (n=2), second cancer (n=5: non-Hodgkin lymphoma, glioblastoma, mesothelioma, colonic adenocarcinoma, esophageal adenocarcinoma), autoimmune disease (n=1), unknown (n=1).
Discussion
One of the real-life outcomes of the successful use of TKI has been the increase in the number of patients living with CML. Estimates of prevalence of CML suggest that more than 100,000 individuals will be on TKI in the USA alone by 2020,22 requiring in excess of 300,000 out-patient
interactions annually. Data from Phase III randomized studies of imatinib versus dasatinib12 and imatinib versus nilotinib11 show that the majority of patients achieve MR3 on at least one occasion by five years (imatinib 64%, dasa- tinib 76% in DASISION; imatinib 60.4%, nilotinib 77% in ENESTnd) and that many of these also reach MR4 or deeper.11,12 Although the cumulative incidences of molecu- lar responses by pre-defined time points are not identical to the achievement of sustained responses, it seems rea- sonable to assume that with continued treatment and changes of treatment for less than optimal responses, the number of patients achieving deep and durable responses will continue to increase.
We used our single center cohort of patients who had reached and sustained for 12 months the ‘safe-haven’ of MR3 to investigate the durability of this response,14 in order to provide some evidence for recommendations for the frequency of PCR monitoring once these deep responses have been established. In using a ‘real-life’ patient cohort, we appreciate that there are complexities of decision-making that are confounding compared to the rigorous clinical trial environment. In clinical practice, many patients are managed on lower than standard doses of the various TKI because of intolerance, some admit to non-compliance so that actual dosing is difficult to esti- mate, and in the early TKI era when only imatinib was available and when the various milestones for response had not been established, some patients were given higher than standard doses to try to deepen their responses. These varying conditions should be taken into account during response monitoring, such that patients may
Figure 2. Patient outcomes. Flow diagram showing outcomes of 450 patients after the achievement of sustained molecular response (MR)-3 (sMR3). The boxes in the lower part of the image contain information about the tyrosine kinase inhibitor (TKI) dose at the time of response loss. LD: lower TKI dose (compared to the stan- dard recommended doses for first or subsequent lines); SD: standard TKI dose; HD: higher TKI dose; sMR4: sustained MR4; pts: patients.
2210
haematologica | 2019; 104(11)