Imatinib Suspension and Validation Study: Results from the Isav Study at 62 Months

Introduction. Imatinib discontinuation in Chronic Myeloid Leukemia (CML) patients (pts) with minimal residual disease is a procedure that allows a treatment free remission in approximately 50% of them. However long term follow-up data are generally missing Here we report an update of the Imatinib Suspension And Validation (ISAV) study at 62 months (mts) of follow-up (FUP).

Aims. The ISAV study is aimed at validating the capability of digital PCR (dPCR) to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR results and to evaluate relapse rate, time of recurrence, survival and the impact of imatinib treatment on Quality of Life (QoL).

Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (Chronic or Accelerated Phase) under imatinib therapy since more than 2 years and in complete molecular remission (CMR) were eligible. Patients had to be in CMR for at least 18 mts, with a minimum of 3 Q-RT-PCR performed at their own sites. After discontinuation of imatinib therapy, Q-RT-PCR was performed monthly (mts 1-6), bimonthly for 36 mts and then every 6 months for additional 2 years, to assess the maintenance of the molecular remission. The loss of molecular remission was defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resumed imatinib treatment at the same dosage used before interruption. Patients' QoL during imatinib discontinuation/resumption was evaluated through the EORTC QLQ-C30 questionnaire.

Results. The ISAV study enrolled 112 pts with a median FUP time of 47.6 mts [95% CI: 42.8-53.0]; 36.6% of them completed the study. The 59.3% of pts were male and 37.0% were aged 65 or older; median duration of imatinib treatment was 103.1 mts with median duration of CMR of 25.4 mts before imatinib discontinuation. dPCR results showed that 23.1% of pts were positive and 75.9% negative at the time of discontinuation, with a Negative Predictive Value ratio (dPCR/Q-RT-PCR) of 1.1 [95% CI: 0.99-1.22]. At 62 mts from imatinib discontinuation, 55 pts (50.9%, 95% CI: 41.1-60.7) of the 108 eligible ones relapsed and resumed imatinib with a relapse rate of 51.9% [95%CI: 42.5-61.0]; 70.9% of them relapsed in the first 9 mts. Of the 53 not-relapsed pts, 40 (37.0% of the total) regained Q-RT-PCR positivity without losing MMR. The median time to Q-RT-PCR positivity was 3.2 mts [95% CI: 2.1-4.6] in the relapsed pts and 4.8 mts [95% CI: 2.9-7.8] in pts who developed only PCR positivity. In this latter group 2 pts experienced late relapses, at 30.6 and 45.5 mts respectively. A loss of CCyR occurred in 13 pts (34.2% of those tested): 10/13 CCyR losses were recovered, the remaining 3 were not be assessed for response. No case of CML progression or resistance to imatinib was observed. After the resumption of imatinib the median time to MMR/CMR was 1.8 [95% CI: 1.1-2.1] mts. One patient, who relapsed, successfully managed a second attempt at discontinuation. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR, Sokal score or duration of CMR was identified, while an inverse relationship between pts age and risk of relapse was evident. Moreover, age and dPCR results together can predict the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥45 years and with negative dPCR (36.1%). The analysis of QoL evidenced a statistically significant improvement in the general well-being and symptoms scales at 1 month after imatinib discontinuation and in particular nausea, diarrhea and fatigue (p<0.01). An inverse and transient trend toward increased pain emerged at mts 1 and 3.

Conclusions. At 62 mts from the beginning of the study, with a median FUP of 47.6 mts, 50.9% of pts relapsed; the majority of relapses developed in the first 9 mts after imatinib discontinuation however late relapses also occurred, up to the 4^th year. Therefore pts who discontinue imatinib should be monitored for a long period of time, especially if they showed positive PCR values after imatinib discontinuation. Age <45 years and dPCR positivity are significantly associated with relapses. QoL analysis showed a significant decrease in symptoms after imatinib discontinuation. Funded by Regione Lombardia.