Intermittent Imatinib (INTERIM) Treatment of Patients with Ph+ Chronic Myeloid Leukemia in Complete Cytogenetic Response: Cytogenetic and Molecular Data At One Year
Authors: Russo Domenico , Baccarani Michele , Martinelli Giovanni , Colombi Chiara , Malagola Michele , Skert Cristina , Soverini Simona , Iacobucci Ilaria , Turri Diamante , Mirto Salvatore , Gobbi Marco , Pierri Ivana , Vitolo Umberto , Pregno Patrizia , Fogli Miriam , Testoni Nicoletta , De Vivo Antonio , Castagnetti Fausto , Morra Enrica , Pungolino Ester , Di Raimondo Francesco , Stagno Fabio , Alimena Giuliana , Breccia Massimo , Nobile Francesco , Martino Bruno , Rambaldi Alessandro , Intermesoli Tamara , Saglio Giuseppe , Cambrin Giovanna Rege , Visani Giuseppe , Nicolini Giuseppina , de Fabritiis Paolo , Abruzzese Elisabetta , Fanin Renato , Tiribelli Mario , Galieni Piero , Bigazzi Catia , Specchia Giorgina , Angelucci Emanuele , Usala Emilio , Musolino Caterina , Russo Sabina , Gaidano Gianluca , Lunghi Monia , Lauria Francesco , Bocchia Monica , Rodeghiero Francesco , D'Emilio Anna , Bosi Alberto , Santini Valeria , Quarta Giovanni , Girasoli Mariella , Fioritoni Giuseppe , Di Lorenzo Roberto , Cesana Bruno , Rosti Gianantonio 
Published: October 2019

Abstract
Abstract 1682

Background:
The introduction of Imatinib has significantly improved the outcome for patients with Ph+ CML. The complete cytogenetic response (CCgR) is a strong and confirmed predictor of improved long-term outcome. According to current recommendations, Imatinib (IM) should be continued indefinitely. However, optimal responders can be eligible for investigational trials of treatment discontinuation.

AIMS:
This study (ClinicalTrials.gov NCT 00858806) describes the effects of a policy of intermittent Imatinib (INTERIM) treatment (one month on/one month off) on cytogenetic and molecular responses in a selected population of patients ≥ 65 years old who were receiving treatment with Imatinib for > 2 years and were in stable complete cytogenetic response (CCgR). The primary endpoint of the study was the proportion of patients who maintained CCgR after 1 year of INTERIM. The secondary endpoint was the level of BCR-ABL transcripts during INTERIM

METHODS:
Cytogenetic and molecular responses were monitored by FISH and RT-Q-PCR every 3 months. The definition of CCgR, and of CCgR loss was based on CBA of marrow metaphases which was performed at baseline and in all the patients who became FISH positive (BCR-ABL–positive nuclei > 1%). Major molecular response (MMR), corresponding to a 3-log reduction in BCR-ABL transcript level from the standardized baseline, was defined as BCR-ABL ≤0.1%IS and was indicated as MR3.0. For the purposes of this study, complete molecular response (CMR) was defined as a 4-log reduction in BCR-ABL transcript level (<0.01%IS), with a sensitivity of at least 10,000 ABL copies, and is indicated as MR4.0. In case of loss of CCgR or MMR, Ph+ additional cytogenetic abnormalities (ACA) and BCR-ABL kinase domain (KD) point mutation analysis were also performed.

RESULTS:
Seventy-six patients have been enrolled. Six patients (8%) lost CCgR (CBA positive), and 3 other patients became FISH positive while remaining CBA negative. At 12 months, the probability of maintaining CBA negativity was 92% (95% CI 86–98%), while the probability of maintaining FISH negativity was 87% (95% CI 79–94%). None of the factors that were examined by univariate and multivariate analysis were found to be associated with an higher probability of either loosing the CCgR (CBA) or showing a FISH positivity (> 1%), with the exception of the duration of imatinib therapy (HR = 0.23, 95% CI 0.008–0.73, P =.01). Among patients with prior Imatinib treatment longer or shorter than 48 months, the probability of maintaining FISH negativity was 94% (95% CI 88–100%) vs 71% (95% CI 53–89%), respectively, HR = 0.23 (P =.007). All the 6 patients who lost CCgR regained the CCgR with daily Imatinib, at the same dose, defined by FISH negativity after 3 to 9 months (4/6 also CBA negative, 2 patients refused bone marrow aspiration). At baseline, all but one patient (99%) were in MMR (MR3.0, BCR-ABL ≤0.1%IS), and 63 patients (83%) were in MR4.0 (<0.01%IS). After one year of intermittent Imatinib, 18/76 patients (24%) lost MR3.0 and 25/63 (39%) patients lost MR4.0. No patient lost complete hematologic response, progressed to accelerated or blastic phase, developed ACA in Ph+ cells, or developed BCR-ABL mutations. After one year, the remaining 70 patients were allowed to go back to continuous treatment, or to continue the intermittent treatment. During the first six months of follow-up (month 13 to 18), 1 of 70 discontinued Imatinib for atrial fibrillation and 9 of 70 went back to continuous treatment because FISH negativity loss (1 patient) or MMR (MR3.0) loss (8 patients). All the patients continue to be regularly observed and monitored and the first twelve months of follow-up will be presented.

CONCLUSIONS:
The intermittent use of imatinib in older patients in stable CCgR after continuous imatinib treatment results in the transient loss of the CCgR in a minority (8%) of the patients. However, the disease burden at the molecular level significantly increased. A policy of intermittent treatment may be an alternative both to chronic continuous treatment and to treatment discontinuation, particularly in the elderly. However, a longer follow up is required before drawing final conclusions.

Acknowledgments:
This work was supported in part by EuropeanLeukemiaNet through the European Treatment and Outcome Study (EUTOS) and by Cofin 2009.

Disclosures:
Baccarani: Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Castagnetti:Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Di Raimondo:celgene: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.