Cytogenetic and Molecular Responses At 3 Months Are Associated with A Better Outcome in Early Chronic Phase (ECP) Chronic Myeloid Leukemia (CML) Patients Treated with Nilotinib.
Authors: Gugliotta Gabriele , Castagnetti Fausto , Palandri Francesca , Breccia Massimo , Levato Luciano , Stagno Fabio , Rege-Cambrin Giovanna , Zaccaria Alfonso , Specchia Giorgina , Usala Emilio , Gozzini Antonella , Martino Bruno , Capucci Adele , Musto Pellegrino , Tiribelli Mario , Abruzzese Elisabetta , Soverini Simona , Bochicchio Maria Teresa , Testoni Nicoletta , Saglio Giuseppe , Martinelli Giovanni , Pane Fabrizio , Alimena Giuliana , Baccarani Michele , Rosti Gianantonio 
Published: October 2019

Abstract
Abstract 2797

Background:
Nilotinib is a second-generation tyrosine kinase inhibitor that demonstrated higher and faster responses and lower progression rates compared to imatinib in ECP CML patients. Early cytogenetic and molecular responses have been associated with a better outcome in patients treated with imatinib, dasatinib, or nilotinib frontline. In particular, BCR-ABL transcript level < 10% at 3 months has been associated with: increased 2-year cumulative incidence of complete cytogenetic response (CCyR), major molecular response (MMR), and MR4.5 (>4.5 log reduction in BCR-ABL transcript level) with dasatinib (Marin D et al, Blood 2012); increased CCyR rate by 1 year, MMR rate by 2 years, and better progression-free survival (PFS) at 2 years, with dasatinib (DASISION; Hochhaus A et al, ASH 2011, abs. 2767); increased MMR rate by 1 year, and better PFS and overall survival (OS), with nilotinib (ENESTnd; Hochhaus A et al, EHA 2012, abs. 584). Here we report a landmark analyses based on BCR-ABL transcript level and cytogenetic response at 3 months to evaluate their impact on subsequent response and outcome in an independent cohort of patients treated with nilotinib-based regimens in Italy (CML Italian Registry of Nilotinib).

Methods:
The CML Italian Registry of Nilotinib includes 215 patients, enrolled in 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) or treated at the Dpt. of Hematology and Oncology, Bologna University Hospital, with nilotinib 300 mg BID or 400 mg BID as initial treatment. The median age was 53 years (range 18–86). The median follow-up was 29 months (range: 18–47 months). At 3 months 196/215 (91%) and 189/215 (88%) patients were evaluable for the molecular and cytogenetic response, respectively. BCR-ABL transcript levels were: 21% in 88%; > 1% to 2 10% in 11%; > 10% in 1%; given the very low proportion of patients with a BCR-ABL > 10% (n. 2), to the purpose of these analyses, patients have been divided into 2 groups, with a transcript level 21% (n. 173, 88%), or > 1% (n. 23, 12%). Cytogenetic response was: CCyR 84%; partial cytogenetic response (PCyR) 9%; less than PCyR 7%. We analyzed the rate of MMR at 1 year, and the failure-free survival (FFS, according to ELN 2009 definitions), PFS (transformation to accelerated or blastic phase), and OS (any death included) according to the BCR-ABL transcript levels and to the cytogenetic response at 3 months.

Results:
Of the 2 patients with a BCR-ABL transcript level > 10% at 3 months, 1 progressed to blastic phase at 1 year, while the other one obtained a CCyR at 6 months and a MMR at 24 months. Patients with BCR-ABL 2 1% at 3 months had a higher rate of MMR at 12 months with respect to those with a transcript level > 1% (79% vs. 35%, p<0.001) (Table 1). A lower transcript level (BCR-ABL 2 1%) at 3 months correlated with a better FFS and PFS and a similar OS at 3 years. Patients with a MCgR and CCyR at 3 months had higher rates of MMR at 12 months (77% and 79%, respectively) vs. patients with less than a MCyR or less than a CCyR (46% and 57%, respectively) (p=0.02 and 0.019, respectively). Patients in MCgR at 3 months had a better FFS and PFS, but similar OS with respect to patients not in MCgR.

Conclusion:
In our national experience, where 42 centers are represented with at least 1 patient, a very small proportion of patients treated frontline with nilotinib failed to achieve a reduction to < 10% level of BCR-ABL transcript (2/196 or 1%) if compared to other reports: in the frame of the ENESTnd trial, 24/258 or 9% (Hochhaus et al, EHA 2012, abs. 584). The cut-off of 1% of BCR-ABL at 3 months in our experience is a reliable surrogate marker of response at 1 year (MMR) and outcome (PFS and FFS), along with the level of cytogenetic response achieved. These patients with > 1% of BCR-ABL at 3 months are characterized by a higher propensity to fail the treatment and to progress. Consequently, they deserve a close monitoring and, for those not achieving the expected cytogenetic and molecular responses later on (at 6–12 months), an optimization of the dose of nilotinib or a treatment modification is advised.

Acknowledgments:
European LeukemiaNet, University of Bologna, BolognAIL, COFIN.

Disclosures:
Gugliotta: Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Abruzzese:Bristol Myers-Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Martinelli:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Speakers Bureau. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.