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4535 Probability of Switch of TKIs Treatment According to Baseline Features in a Large Chronic Myeloid Leukemia (CML) Population: Italian CML Network

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Adult, Clinical Practice (Health Services and Quality), Therapy sequence, Treatment Considerations, Study Population, Human, Measurable Residual Disease
Monday, December 9, 2024, 6:00 PM-8:00 PM

Massimo Breccia1*, Valentina Giai, MD, PhD2*, Tiziana Rosso, PhD3*, Patrizia Pregno, MD4*, Fausto Castagnetti, MD, PhD5, Massimiliano Bonifacio, MD6,7*, Isabella Capodanno, MD8*, Mario Tiribelli, MD9*, Fabio Stagno, MD, PhD10, Olga Mulas, MD11*, Antonella Gozzini, MD12*, Luigiana Luciano, MD13, Sara Galimberti, MD14*, Andrea Patriarca, MD15*, Giuseppe Lanzarone, MD16*, Bruno Martino, MD17*, Anna Guella, MD18*, Anna Rita Scortechini, MD19*, Carmen Fava, MD, PhD20,21*, Claudio Fozza, MD22*, Federica Sorà, MD23*, Alessandro Maggi24*, Michele Pizzuti, MD25*, Sara Freducci, MD26*, Giuseppina Loglisci, MD27*, Antonella Russo Rossi, MD28*, Maria Laura Di Noi, MD29*, Giuseppina Spinosa, MD30*, Maria Teresa Santeramo, MD31*, Grazia Sanpaolo, MD32*, Giuseppe Pietrantuono, MD33*, Clara Mannarella, MD34*, Elisabetta Calistri, MD35*, Eleonora Prete, MD36*, Gianantonio Rosti, MD37*, Fabrizio Pane38, Giuseppe Saglio, MD39, Giovannino Ciccone, MD3* and Giorgina Specchia, MD, PhD40

1Department of Translational and Precision Medicine, Az., Hematology-Sapienza University, Rome, Italy
2Hematology, AOU Città della Salute e della Scienza di Torino, Turin, Italy
3Clinical Epidemiology Unit and CPO Piemonte, Città della Salute e della Scienza, Turin, Italy
4Former Haematology Unit, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy, TORINO, ITA
5Department of Medical and Surgical Sciences, Institute of Hematology “Seràgnoli”, University of Bologna, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
6Department of Engineering for Innovation Medicine, Section of Innovation Biomedicine, Hematology Area, University of Verona, Verona, Italy
7U.O.C. di Ematologia, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
8Hematology Department, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Reggio Emilia, Italy
9Division of Hematology and BMT, Department of Medical Area, University of Udine, Udine, Italy
10Hematology Section AOU Policlinico “ G.Martino , University of Messina Italy, Messina, Italy
11Department of Medical Sciences and Public Health, University of Cagliari, Businco Hospital, Cagliari, Italy
12Hematology, AOU Careggi, University of Florence, Florence, Italy
13Hematology Unit, Federico II University, Napoli, Italy
14Department of Clinical and Experimental Medicine, Hematology, University of Pisa, Pisa, Italy
15Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont and Maggiore Charity Hospital, Novara, Italy
16Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Turin, Turin, Italy
17Division of Hematology, Azienda Ospedaliera 'Bianchi Melacrino Morelli', Reggio Calabria, Italy
18Hematology Unit, Santa Chiara Hospital, APSS Trento, Trento, Italy
19Division of Hematology, Department of Molecular and Clinical Sciences, University of Marche, Ancona, Italy, Ancona, Italy
20Hematology, Mauriziano Hospital, Torino, Turin, Italy
21Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
22Hematology Unit – Azienda Ospedaliera Universitaria of Sassari, University of Sassari, Sassari, Italy
23Institute of Hematology, Policlinico Universitario A. Gemelli, “Cattolica” University, Rome, ROME, Italy
24Division of Hematology and Bone Marrow Transplant, Ospedale S.G. Moscati, Taranto, Italy
25Department of Onco-Hematology, “San Carlo” Regional Hospital, Potenza, Italy
26Haematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy
27Department of Hematology, Ospedale Vito Fazzi, Lecce, Italy
28MD Department of Precision and Regenerative Medicine and Ionian Area, "Aldo Moro" University School of Medicine, Bari, Italy
29Hematology, Hospital A. Perrino, Brindisi, Italy
30Hematology Unit, Policlinico Riuniti Ospedaliero Universitario, Foggia, Italy
31Hematology Unit - Ospedale "Mons. Dimiccoli", Barletta, Italy, Barletta, Italy
32Hematology Unit, IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy
33Hematology and Stem Cell Transplantation Unit, IRCCS Centro Oncologico della Basilicata, Rionero in Vulture, Italy
34Hematology Unit, Ospedale Madonna delle Grazie, Matera, Italy
35Division of Hematology - Dipartimento Medicina Clinica 1 - Ospedale San Giacomo Apostolo, Treviso, ITA
36Hematology Unit, Azienda C. Panico, Tricase, Italy
37Medical Oncology Unit, IRST/IRCCS “Dino Amadori,”, Meldola (FC), Italy
38Department of Hematology and Bone Marrow Transplantation, University Hospital Federico II, Naples, Italy
39Dept. of Clinical and Biological Sciences, University of Turin, Turin, Italy
40Former Full Professor of Hematology, University of Bari, Bari, Italy

Introduction

The outcome of CML patients in chronic phase (CP) has deeply changed over time after the introduction of TKIs and life expectancy is near to that of general population. Although the outstanding results obtained, 20-30% of patients still experienced resistance and/or intolerance and need a change of treatment. How to identify those patients at risk of therapeutic switch during treatment remain a matter of discussion.

Methods

The CML Italian network (including 68 Hematology Centers from 19 Italian regions) prospectively recorded in a dedicated web-based database (https://www.epiclin.it/lmc) the clinical and biological features of all newly diagnosed Italian adult (>18 years) Ph+ CML patients in each phase of disease, diagnosed from January 2013 onwards. All consecutive patients were included, without any exclusion criteria and regardless of their participation in any other clinical trial, to limit the eligibility criteria selection typical of experimental studies. Baseline information included sociodemographic, clinical, and standard laboratory data. For this analysis, patients prospectively collected from 33 centers with updated follow-up data were considered. Fine and Gray multivariable models were used to estimate the adjusted sub hazard ratios (HR) of the first and second change of therapy, considering competitive events.

Results

1433 patients (57% males) prospectively enrolled were analyzed: of them, 702 initially treated with imatinib and 731 with second generation TKIs (2gen TKI). ELTS stratification showed 59.4% of patients as low risk, 28% as intermediate and 12% as high risk. The baseline Charlson comorbidity index detected 71% as score 2 and the remaining as score ≥ 3. The median follow-up was 4.6 years with most patients aged 61-70 years (23%). In the whole cohort, 55% of patients presented concomitant comorbidities, with most represented being cardiovascular (CV) in 27% of patients. Two-hundreds and nine patients (14.5%) had cytogenetic aberrations at baseline. In the imatinib treated cohort, 32% of patients were aged 71-80 years and 39% presented CV initial comorbidities. In the 2gen TKI cohort, 56.8% of patients aged between 41 and 60 years received frontline nilotinib or dasatinib with only 15% of them presenting baseline CV comorbidities. The overall survival of the whole cohort at 5 years was 88%. Out of 428 patients who deserve a second line, 212 (49.5%) switched for resistance to 1st line (at 2 years: 18.7% for Imatinib and 8.9% for 2gen TKI). The statistical analysis revealed a hazard ratio (HR) for first switching for resistance of 0.34 (0.25-0.47, p<0.0001) for those starting with a 2gen TKI, a reduction of the risk with increasing age (HR 0.97 per year, 0.96-0.98, p<0.0001), and increased risk for intermediate (1.79, 1.27-2.53, p=0.001) and high ELTS risk (2.87, 1.90-4.34, p<0.0001) compared to low risk. One hundred and forty-three patients (33.5%) switched for intolerance. The analysis showed an increased risk for patients who started with a 2gen TKI (1.90, 1.26-2.84, p=0.002), and a trend for a positive association for females (1.37, 0.98-1.91, p=0.064) and for increasing age (1.1 per year, 0.99-1.03, p=0.056).

A second change of treatment was recorded in 119 patients (40% for resistance). Factors predicting a lower risk of resistance were starting with 2gen TKI vs imatinib (0.45, 0.21-0.95, p=0.035), and increasing age (0.96 per year, 0.94-0.98, p<0.0001), while high ELTS risk (3.64, 1-76-7.54, p=0.001) was predictive for a second change. Fifty-five patients changed for intolerance and the analysis revealed a significant reduction in those starting with 2gen TKI vs imatinib (0.48, 0.25-0.93, p=0.030) and high ELTS risk vs low (2.75, 1.33-5.70, p=0.006).

Conclusions

The results of the analysis showed that the time to first treatment switch for resistance is shorter for younger patients, for those initially treated with imatinib, and for intermediate/high ELTS risks. The risk of switch for intolerance is higher for patients initially treated with 2genTKIs and, possibly, for females and with increasing age. The different factors associated to treatment switch for resistance or intolerance may help physicians and patients to make more informed decisions in the choice of the initial treatment.

Disclosures: Breccia: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; BMS: Honoraria; AOP: Honoraria; GSK: Honoraria. Giai: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bonifacio: BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; 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. Stagno: Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Mulas: Novartis: Speakers Bureau. 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; AbbVie: Honoraria, Other: support for attending meetings; Pfizer: Honoraria; Janssen: Honoraria. Patriarca: Novartis: Honoraria; Takeda: Honoraria; Alexion: Honoraria, Other: Alexion Hospitality at ASH 2022; Incyte: Honoraria; Pfizer: Honoraria; Sanofi: Consultancy, Honoraria, Other: Sanofi Hospitality at EHA 2022; Sanofi Hospitality at EHA 2021; Sobi: Consultancy, Honoraria, Other: Sobi Hospitality at ASH 2023; BMS: Honoraria. Martino: Incyte: Speakers Bureau; AstraZeneca: Speakers Bureau; Novartis: Speakers Bureau; Janssen: Speakers Bureau. Fozza: Soby: Consultancy; Sanofi: Research Funding; BMS: Research Funding; Amgen: Research Funding. Sorà: Novartis: Research Funding. Rosti: Novartis: Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Pane: GSK Incyte Amgen BMS Janssen Jazz Novartis Pfizer: Speakers Bureau; GSK Incyte: Consultancy. Saglio: Hikma: Speakers Bureau; Ascentage Pharma: Consultancy; Novartis: Consultancy, Speakers Bureau.

*signifies non-member of ASH