Nilotinib 300 Mg Twice Daily as First Line Treatment of Ph-Positive Chronic Myeloid Leukemia In Chronic Phase: Updated Results of the ICORG 0802 Phase 2 Study with Analysis of the GeneXpert System Versus IS BCR-ABL RQ PCR.
Authors: Conneally Eibhlin , Swords Ronan T , Giles Francis J. , McMullin Mary Frances , Coutre Philipp le , Langabeer Stephen , Wieczorkowska Marzena , McDowell Cliona , Moulton Brian , Egan Karine , O'Dwyer Michael 
Published: October 2019

Abstract
Abstract 3427
Recently, early results of the ENESTnd phase III trial showing superiority of nilotinib over imatinib, led to accelerated approval of Nilotinib as initial treatment of ECP CML at a dose of 300mg BID. Independently, since December 2008, ICORG, the All-Ireland Cooperative Oncology Research Group has been conducting an open-label, single stage, multicenter, phase II study (ClinicalTrials.gov NCT00809211) to investigate the safety and efficacy of nilotinib 300 mg BID in untreated, ECP, Ph-pos CML patients. The primary endpoint is the CCyR rate at 6 months; secondary endpoints include the kinetics of molecular response, determined by RQ-PCR at baseline and 3 monthly from start of treatment as well as an evaluation of a new rapid turnaround PCR system “GeneXpert” with IS BCR-ABL RQ-PCR. To date a total of 37 patients have been enrolled on the trial. The median age of these 37 patients is 51 (range 20 –77); 50% have low risk Sokal score, 22% intermediate and 28% high risk. Median follow up is currently 8 months (range 1–17) with 25 patients evaluable for response following at least 3 months on study.

Results:
By intent to treat analysis the CCyR rate is 64% (16/25) at 3 months and 95% (19/20) at 6 months, with all patients actually tested Ph negative by 6 months. By 6 months 12/20 patients have achieved MMR (60%). This analysis includes 1 patient with variant transcripts and 2 patients bordering on MMR at 3 months who had insufficient RNA for analysis at 6 months. While none of the patients have progressed on study, three patients are now off the study: persistent grade 3 thrombocytopenia in one, persistent LFTS abnormalities in a second case and one death due to progressive multiple system atrophy, which was unrelated. 3 of 25 patients (12%) have undergone dose escalation to 400mg BID for suboptimal response. The median daily dose was 600mg; 16/34 (47%) have interrupted nilotinib at least once with a median duration of interruption of 0.5 days. The dose of nilotinib at the last visit was > 300mg BID in 82% (28/34). Haematologic toxicity was minimal with grade III thrombocytopenia seen in 2 patients (5%). Grade III non-haematologic toxicity included an elevated lipase in 6/36 (17%). The only other grade III toxicities noted were musculo-skeletal pain and an elevated ALT in 1 patient each. Analysis of 71 follow-up paired samples from 21pts at 3 monthly intervals by “GeneXpert” and RQ-PCR showed an encouraging correlation between the methodologies. At 3 months the median BCR-ABL/ABL % was 0.45 as calculated by “GeneXpert” and 0.67 by IS RQ-PCR and at 6 months 0.06 and 0.01 respectively. However in individual patients, there was a trend for “GeneXpert” to underestimate Bcr-Abl/Abl % and therefore overestimate attainment of MMR.

Conclusion:
In this preliminary analysis, nilotinib 300mg BID induces high rates of CCyR and MMR equivalent to those reported previously in the phase II and III studies of nilotinib in ECP CML. This trial provides independent confirmation that nilotinib 300mg BID is safe and effective treatment for ECP CML. “GeneXpert” provides rapid results both at diagnosis and follow–up and would be further enhanced by calculation of a conversion factor to the IS scale.

Disclosures:
Conneally: Novartis: Honoraria. Giles:Novartis: Consultancy, Honoraria. Egan:Novartis: Employment. O'Dwyer:Novartis: Honoraria.