3-YEARS and Beyond Study Completion Results of the Otpkima Randomized Clinical Trial in Elderly CML Patients
Authors: Malagola Michele , Iurlo Alessandra , Bucelli Cristina , Abruzzese Elisabetta , Bonifacio Massimiliano , Stagno Fabio , Binotto Gianni , D'Adda Mariella , Lunghi Monia , Crugnola Monica , Ferrari Maria Luisa , Lunghi Francesca , Castagnetti Fausto , Rosti Gianantonio , Lemoli Roberto Massimo , Sancetta Rosaria , Coppi Maria Rosaria , Corsetti Maria Teresa , Dalmazzo Matteo , Romano Atelda , Tiribelli Mario , Russo Rossi Antonella , Russo Sabina , Sicuranza Anna , Roccaro Aldo , Butturini Giulia , Farina Mirko , Bernardi Simona , Pellizzeri Simone , Polverelli Nicola , Russo Domenico 
Published: December 2023

The goal of Treatment Free Remission (TFR) is achievable in no more than 25-30% of patients with Ph+ Chronic Myeloid Leukemia (CML) treated with Tyrosine Kinase Inhibitors (TKIs). Thus, for the great majority of patients, particularly for the elderly, the options are to continue TKI therapy life-long or to enter an intermittent TKI administration, as previously published ( Russo D et al, Blood 2013; Russo et al Blood Adv 2015). The probability of major molecular response (MMR or MR3.0) maintenance while on intermittent 1 month on/1 month off TKI at 1 year is 80%, as reported recently in the first interime analysis of the Italian prospective randomized OPTkIMA trial (Malagola M et al, Cancer Med 2021).
This is the second interim report of OPTkIMA trial, in which elderly patients with Ph+ CML in sustained (≥ 2 years) confirmed major molecular response (MMR or MR3.0) or deep molecular response (MR4.0 or deeper) were randomly assigned to receive a FIXED intermittent schedule (1 month on/1 month off) vs a PROGRESSIVE intermittent schedule (1 month on/1 month off for the 1 st year, 1 month on/2 months off for the 2 nd year, 1 month on/3 months off for the 3 rd year). After the 3 rd year, clinicians were free to decide if maintain the intermittent schedule, discontinue TKI or resume TKI daily ( Malagola M et al, Cancer Med 2021).
At last follow up, 203 patients are evaluable after randomization (104 FIXED vs 99 PROGRESSIVE). At 3 rd year (end of study protocol), by intention to treat, 28/104 (27%) and 45/99 (45%) patients discontinued OPTkIMA because of MR3.0 loss in the FIXED vs PROGRESSIVE arm, respectively (p=0.005). The percentages of patients who discontinued OPTkIMA because of MR3.0 loss at 1 st, 2 nd and 3 rd year in the FIXED vs PROGRESSIVE arm were: 24% in both arms (p=0.97), 1% vs 22% (p=0.001) and 3% vs 15% (p=0.01), respectively (Figure 1). The probability of survival without MR3.0 loss at 1, 2 and 3 years in the FIXED vs PROGRESSIVE arm were: 81%, 69% and 66% vs 81%, 59% and 53%, respectively (Figure 2; p=0.13). None of the patients who lost MR3.0 progressed to accelerated or blastic phase (AP/BP) and all of the patients regained the MR3.0 after continuous TKI resumption within 9 months.
At the end of the 3 rd year from randomization, 61/104 (59%) and 36/99 (36%) patients were in MR3.0 or deeper response in the FIXED vs PROGRESSIVE arm, respectively (p=0.001). For these patients, comparing the two arms, Clinicians' choice was to maintain the ongoing intermittent schedule in 46% vs 28% of the cases (p=0.01), discontinue TKI with the goal of TFR in 36% vs 58% (p=0.03), and resume the TKI continuously in 18% vs 14% of the patients (p=0.59).
The results of the OPTkIMA trial clearly confirm that a policy of intermittent TKI administration in elderly patients with Ph+ CML in MR3.0 or deeper response is safe, as no progression to AP/BP was observed. Furthermore, the great majority of protocol discontinuation for MR3.0 loss were recorded in the 1 st year (one month on and one month off in both arms). Then the cumulative incidence of patients who lost MR3.0 beyond the 1 st year was significantly higher in the PROGRESSIVE arm with a trend towards a higher probability of survival without MR3.0 loss in the FIXED arm (Figure 1). Finally, at the end of the study protocol (3 rd year), patients in MR3.0 or deeper response after a FIXED intermittent schedule were more likely addressed to maintain the same program, whereas patients included in the PROGRESSIVE arm were more frequently discontinued with the goal of TFR. This last observation represents a “real-life” CML management by Clinicians. It suggests that after a PROGRESSIVE intermittent therapy, patients were considered at high probability to safely maintain the TFR.