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3162 Tyrosine Kinase Inhibitors Discontinuation in Chronic Myeloid Leukemia: Observational Study of 673 Patients in Italy

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical Practice (Health Services and Quality), Clinical Research, Real-world evidence, Measurable Residual Disease
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Valentina Bonuomo, MD1*, Emanuele Koumantakis2*, Selene Grano, MD3*, Paola Berchialla, PhD4*, Fausto Castagnetti, MD, PhD5, Bruno Martino, MD6*, Chiara Elena, MD7*, Monica Bocchia, MD8*, Isabella Capodanno, MD9*, Tamara Intermesoli10*, Maria Cristina Miggiano11*, Carlo Gambacorti-Passerini, MD, Prof.12, Alessandra Iurlo, MD, PhD13*, Francesca Lunghi14*, Luigiana Luciano, MD15, Elisabetta Abruzzese, MD16, Angelo Michele Carella, MD17*, Massimo Breccia18*, Felicetto Ferrara, MD19*, Sabrina Leonetti Crescenzi, MD20*, Barbara Scappini21*, Marco De Gobbi, MD, PhD22*, Federica Sorà23*, Davide Rapezzi, MD24*, Debora Luzi, MD25*, Sara Galimberti, MD26*, Monica Crugnola, MD27*, Anna Rita Scortechini, MD28*, Alessandro Maggi29*, Massimiliano Bonifacio, MD30*, Mario Annunziata, MD31*, Giovanni Caocci, MD32, Germana Beltrami, MD33*, Francesco Cavazzini, MD34*, Giuseppe Pietrantuono, MD35*, Leonardo Campiotti36*, Fabio Stagno, MD, PhD37, Caterina Musolino38*, Daniela Cilloni, MD39*, Giuseppe Saglio, MD40 and Carmen Fava, MD, PhD41*

1Department of Clinical and Biological Sciences, University of Turin, Rivoli, Italy
2Universita' Degli Studi Di Torino UNITO, Torino, ITA
3Department of Molecular Biotechologies and Health Sciences, University of Torino, Turin, ITA
4Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy
5Department of Medical and Surgical Sciences, Institute of Hematology “Seràgnoli”, University of Bologna, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
6Division of Hematology, Azienda Ospedaliera 'Bianchi Melacrino Morelli', Reggio Calabria, Italy
7U.O.C Ematologia 1, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
8Hematology Unit, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Siena, Italy
9hematology, AUSL Reggio Emilia, Reggio Emilia, Italy
10Hematology and Bone Marrow Transplant Unit, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
11Hematology Department, San Bortolo Hospital, Vicenza U.O.C. di Ematologia, Vicenza, ITA
12Department of Medicine and Surgery, University Milano-Bicocca, Monza, Italy
13Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
14San Raffaele Institute Milano Italy, Milano, ITA
15Hematology Unit, Federico II University, Napoli, Italy
16Department of Hematology, S. Eugenio Hospital, Tor Vergata University, ASL Roma 2, Roma, I, Italy
17Department of Hematology/Oncology, IRCCS, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy, San Giovanni Rotondo (FG), Italy
18Department of Translational and Precision Medicine, Az., Hematology-Sapienza University, Rome, Italy
19Division of Hematology, AORN Cardarelli, Naples, Napoli, Italy
20Division of Hematology, Azienda Ospedaliera San Giovanni Addolorata, Roma, Italy
21Hematology Unit, Hematology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
22Department of Clinical and Biological Sciences, Department of Clinical and Biological Sciences, University of Turin, Orbassano, ITA
23Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
24Department of Hematology, S. Croce e Carle Hospital, Cuneo, Italy
25Onco-Hematology Department, AO Santa Maria, Terni, Terni, Italy
26Department of Clinical and Experimental Medicine, Hematology, University of Pisa, Pisa, Italy
27Hematology Unit, University of Parma, Parma, Italy
28Division of Hematology, Department of Molecular and Clinical Sciences, University of Marche, Ancona, Italy, Ancona, Italy
29Division of Hematology and Bone Marrow Transplant, Ospedale S.G. Moscati, Taranto, Italy
30Department of Engineering for Innovation Medicine, Section of Innovation Biomedicine, Hematology Area, University of Verona, Verona, Italy
31Hematology, San Giuseppe Moscati Hospital, Aversa, Italy
32University of Cagliari, Monserrato, Italy
33U.O. Ematologia e terapie cellulari, IRCCS Azienda Ospedaliera Universitaria San Martino, Genova, Italy
34Division of Hematology, Arcispedale Sant'Anna, University of Ferrara, Ferrara, ITA
35Hematology and Stem Cell Transplantation Unit, IRCCS Centro Oncologico della Basilicata, Rionero in Vulture, Italy
36Department of Medicine and Surgery, University of Insubria, Varese, ITA
37Hematology Section, Biomedical Sciences, Trecastagni, Catania, Italy
38Division of Hematology, Department of Human Pathology in Adulthood and Childhood, University of Messina, Messina, Italy
39Department of Clinical and Biological Sciences, University of Turin, Orbassano, ITA
40Dept. of Clinical and Biological Sciences, University of Turin, Turin, Italy
41Department of Clinical and Biological Sciences, University of Turin, Turin, Italy

Background: Treatment free remission (TFR) is one of the main goals of therapy with tyrosine kinase inhibitors (TKIs) in Chronic Myeloid Leukemia (CML) patients (pts). In the last 15 years several studies analyzed the outcome of pts who discontinued TKIs demonstrated that it is safe according to the current recommendations.

Aims: to evaluate TFR in the setting of clinical practice for bringing out unmet clinical needs, optimizing already consolidated practices and obtaining increasingly personalized treatments based on the disease profile.

Methods: we proposed a retrospective and prospective observational study on pts with CML who discontinued TKIs in Italy. We performed descriptive statistics and survival analysis with Kaplan-Meier. Bayesian Model Averaging (BMA) was used to assess potential risk factors. BMA averages all data-supported models to estimate effect sizes of variables on the endpoint. The percentage of inclusion (PI) indicates how often a variable appears across models, suggesting its importance. Standard rules of thumb for interpreting this posterior probability are P<50% evidence against the effect; 50-75% weak evidence; 75-95% positive evidence; >95% strong evidence.

Results: We present data on the first 673 pts who discontinued TKIs in 43 centers. Median age at discontinuation was 59 yo (IQR:48-70). 313(46.5%) were female; 53%, 34.5% and 13.5% were low, intermediate, and high Sokal score respectively. 27.5% pts carried a b2a2 BCR-ABL1 transcript, 70.4% pts a b3a2 and 12 pts discontinued with an atypical transcript. 497 pts (74.6%) discontinued in first line, 148 pts in 2nd line, 18 pts in 3rd line, and 3 pts in fourth line. 387 pts (57.5%) were on treatment with imatinib at discontinuation, of which 362 pts (94.5%) frontline. 179 pts (26.6%) with nilotinib (113 frontline, 66 in 2nd or further lines), 91 pts (13.5%) with dasatinib (22 frontline, 67 in 2nd or further lines), 11 pts (1.6%) with bosutinib and 5 pts discontinued ponatinib in 2nd or further lines.

Median duration of treatment with the last TKI was 82 mos (IQR:56-118); median time to DMR (undetectable transcript or MR4/MR4.5/MR5) with the last TKI was 17.5 mos (IR 7.8-35). Median duration of DMR was 63 mos (IQR:39-91) before suspension. 620 pts had a response defined according to molecular standardization: 6 pts (0.9%) were less than MMR, 29 pts (4.7%) were MR3, 181 pts (29.2%) were MR4, 223 pts (36%) were MR4.5, 181 pts (29.2%) were MR5. Reasons for discontinuation were toxicity for 117 (17.8%) of pts, pregnancy for 33 (5%), shared decision between clinician and patient for 440 (66.9%), other reasons for 68 pts (10.3%). Median time to restart treatment was 5.3 mos (IQR: 3.7-10).

187 pts had to restart therapy, 118 (63.1%) were treated with imatinib, 39 (20.9%) with nilotinib, 21 (11.2%) with dasatinib, 7(3.7%) with bosutinib, 2 pts (1.1%) with ponatinib. 160 pts (85.6%) restarted treatment with the same TKI that was ongoing before discontinuation. One patient restarted treatment with asciminib. One patient progressed in accelerated phase and another one patient had a lymphoid blastic crisis.

We assessed age at discontinuation, sex, Sokal score, ELTs risk, type of transcript, duration of TKI therapy, line of therapy at stop, last TKI generation, depth of MR, reasons for stop as potential prognostic factors for TFR. We have identified as risk factors associated for restarting treatment the last TKI (2nd or 3rd gen vs 1st gen HR = 0.51, P>99%), it means that those who discontinue a 2nd or 3rd gen TKIs have a 49% reduction of the risk of resuming treatment, regardless of the line of therapy; the duration of DMR (1% risk reduction for any additional month, HR = 0.99, P>99%), level of MR at stop (PI=38%) (MR4.5 vs MR4, HR:0.51, P = 99%, MR5 vs MR4, HR:0.52, P=99%), the duration of the TKIs therapy before discontinuation (PI=44%) with HR:0.99, meaning that for each additional month there is a risk reduction of 1%, P=97%).

Survival analysis was conducted on 655 patients. 187 pts (28.5%) had to resume therapy, most of them (N=151) lost molecular response within 12 months of stopping treatment.

Conclusions: Respect to our previous study on 283 pts, we confirm the importance of treatment duration and of the type of TKI as prognostic factors for TFR maintenance. For the first time 2 pts progressed, suggesting that we need to explore other alerts aimed at early detection of those who, despite meeting the criteria for TFR, have an increased risk of resuming treatment.

Disclosures: Martino: Janssen: Speakers Bureau; Novartis: Speakers Bureau; AstraZeneca: Speakers Bureau; Incyte: Speakers Bureau. Bocchia: Novartis: Honoraria, Other: travel grant; Incyte: Honoraria, Other: travel grant; Abbvie: Honoraria, Other: travel grants. Capodanno: Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau. Iurlo: GSK: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; AOP: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Abruzzese: MorphoSys: Consultancy; Ascentage: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; BMS: Consultancy. Breccia: AOP: Honoraria; GSK: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; BMS: Honoraria; Novartis: Honoraria. Galimberti: Celgene: Honoraria; Roche: Honoraria, Other: support for attending meetings; Incyte: Honoraria; Novartis: Honoraria, Other: support for attending meetings; Jazz: Honoraria, Other: support for attending meetings; AstraZeneca: Honoraria, Other: support for attending meetings; Pfizer: Honoraria; AbbVie: Honoraria, Other: support for attending meetings; Janssen: Honoraria. Crugnola: Novartis: Speakers Bureau; BMS: Speakers Bureau. Bonifacio: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Stagno: Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Saglio: Ascentage Pharma: Consultancy; Hikma: Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

*signifies non-member of ASH