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3155 CML Patients Who Fail to Achieve ≤ 1% BCR::ABL1 at 12 Months or ≤ 0.1% BCR::ABL1 at 24 Months (major molecular response, MMR) Show Significantly Inferior Survival, but Not Due to CML-Related Deaths: Data from an Italian Real-Life Observational Study

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

Valentina Giai, MD, PhD1*, Tiziana Rosso, PhD2*, Fausto Castagnetti, MD, PhD3, Patrizia Pregno, MD4*, Massimiliano Bonifacio, MD5,6*, Isabella Capodanno, MD7*, Mario Tiribelli, MD8*, Fabio Stagno, MD, PhD9, Giovanni Caocci, MD10, Antonella Gozzini, MD11*, Luigiana Luciano, MD12, Sara Galimberti, MD13*, Monica Bocchia, 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*, Simona Sica, MD, PhD23*, Nicola Di Renzo24*, Pellegrino Musto, MD25*, Domenico Pastore, MD26*, Alessandro Maggi, MD27*, Michele Pizzuti, MD28*, Lorella Maria Antonia Melillo, MD29*, Angelo Michele Carella, MD30*, Giuseppe Tarantini, MD31*, Anna Mele, MD32*, Elisabetta Calistri, MD33*, Maria Rosaria Coppi, MD26*, Fabio Saccona34*, Emilia Scalzulli, MD35*, Beatrice Battaglio, MD6*, Miriam Iezza, MD36*, Cinzia Bitetti, MD37*, Roberto Freilone, MD38*, Gianantonio Rosti, MD39*, Francesco Albano, MD40*, Fabrizio Pane41, Giorgina Specchia, MD, PhD42, Massimo Breccia43*, Giovannino Ciccone, MD2* and Giuseppe Saglio, MD44

1Hematology, AOU Città della Salute e della Scienza di Torino, Turin, Italy
2Clinical Epidemiology Unit and CPO Piemonte, Città della Salute e della Scienza, Turin, Italy
3Department of Medical and Surgical Sciences, Institute of Hematology “Seràgnoli”, University of Bologna, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
4Former Haematology Unit, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy, TORINO, ITA
5Department of Engineering for Innovation Medicine, Section of Innovation Biomedicine, Hematology Area, University of Verona, Verona, Italy
6Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
7hematology, AUSL Reggio Emilia, Reggio Emilia, Italy
8Division of Hematology and BMT, Department of Medical Area, University of Udine, Udine, Italy
9Hematology Section AOU Policlinico “ G.Martino , University of Messina Italy, Messina, Italy
10University of Cagliari, Monserrato, Italy
11Hematology, AOU Careggi, University of Florence, Florence, Italy
12Hematology Unit, Federico II University, Napoli, Italy
13Department of Clinical and Experimental Medicine, Hematology, University of Pisa, Pisa, Italy
14Hematology, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, 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
23Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Sacro Cuore, Rome, Italy
24"Vito Fazzi" Hospital, Hematology and Stem Cell Transplant Unit, Lecce, Italy
25Department of Precision and Regenerative Medicine and Ionian Area, "Aldo Moro" University School of Medicine, Bari, Italy; Hematology and Stem Cell Transplantation Unit, AOU Consorziale Policlinico, Bari, Italy, Bari, Italy
26Hematology and Bone Marrow Transplant Unit, Brindisi, Italy, Brindisi, Italy
27Division of Hematology and Bone Marrow Transplant, Ospedale S.G. Moscati, Taranto, Italy
28Department of Onco-Hematology, “San Carlo” Regional Hospital, Potenza, Italy
29Hematology and Stem Cell Transplantation Unit, Policlinico Riuniti Foggia, Foggia, Italy
30Department of Hematology/Oncology, IRCCS, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy, San Giovanni Rotondo (FG), Italy
31Haematology, Ospedale "Mons. Dimiccoli", Barletta, Italy
32Hematology Unit, Azienda C. Panico, Tricase, Italy
33Division of Hematology - Dipartimento Medicina Clinica 1 - Ospedale San Giacomo Apostolo, Treviso, ITA
34Clinical Epidemiology Unit and CPO Piemonte, Città della Salute e della Scienza, Torino, Italy
35Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Roma, Italy
36Istituto di Ematologia "Seràgnoli", IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
37Hematology, Presidio Ospedaliero “Madonna delle Grazie”, Matera, Italy
38Hematology, Department of Hematology and Oncology, Città della Salute e della Scienza di Torino, Torino, Italy
39IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola (FC), Italy
40Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Hematology and Stem Cell Transplantation Unit, University of Bari "Aldo Moro", Bari, Italy
41Division of Hematology and SCT Unit, Federico II University, Naples, Naples, Italy
42Former Full Professor of Hematology, University of Bari, Bari, Italy
43Department of Translational and Precision Medicine, Az., Hematology-Sapienza University, Rome, Italy
44Dept. of Clinical and Biological Sciences, University of Turin, Turin, Italy

Introduction

The achievement of CCyR (complete cytogenetic response) or of the corresponding BCR::ABL1 ≤1% molecular value is generally accepted as the goal to be achieved for a good survival, but the time to achieve this goal and the relevance for survival of achieving deeper molecular responses such as MMR (BCR::ABL1≤0.1% value) are still under discussion. In order to clarify these aspects we studied the database of the Italian CML Network, that prospectively enroll all adult CML patients from 68 Italian hematology centers since January 2013 (https://www.epiclin.it/lmc).

Methods and Results

A total of 1433 patients with updated follow-up data were included in this analysis. Baseline information included sociodemographic, clinical, and standard laboratory data. 702 patients were treated with first-line imatinib and 731 with second-generation (2ndG) TKIs (414 with nilotinib, 312 with dasatinib and 5 with bosutinib). The two cohorts show a relevant difference in median age: 70 years for the imatinib cohort and 52 years for the 2ndG cohort. The ELTS risk score stratification is also different: in the imatinib cohort, low risk (LR) patients are 51%, intermediate risk (IR) 35% and high risk (HR) 14%, whereas in the 2ndG TKIs cohort, LR patients are 68%, IR 21% and HR 11%.

The 5-year survival for the overall population is 88% with 22 of 133 deaths (16.5%) due to CML-related causes (progression to blast crisis). Due to the difference in median age, the 5-year survival in the imatinib arm is 82%, with 9 of 98 total deaths (9%) due to CML, while the 5-year survival in the 2ndG TKI arm is 94%, with 13 of 35 (37%) deaths due to CML. All but 4 progressions and most CML-related deaths occur within the first 2 years of therapy. 11 of 22 (50%) CML-related deaths occur in the HR group (175 patients, 12% of the total), compared to 8 in the IR group (404 patients, 28%) and only 3 in the LR group (852 patients, 60%). Therefore, regardless of the treatment received, the risk of CML-related death is approximately 6% in the HR group, 1.98% in the IR group, and only 0.35% in the LR group. The ELTS risk score at diagnosis discriminates survival probabilities very well in both treatment cohorts: in the imatinib cohort, survival over 5 years was LR 92%, IR 74% and HR 66% and in the 2ndG TKIs treated cohort survival was LR 97%, IR 91%and HR 82%. In the imatinib-treated cohort, molecular response is associated with a statistically significant inferior survival for those patients not achieving BCR::ABL1 ≤ 1% at 12 months (P value <0.0001) or ≤ 0.1% at 24 months (P value = 0.0002), but the occurrence of CML-related deaths is not significantly associated with molecular response. Although less marked, also in the 2ndG TKI group, survival is significantly inferior in patients who do not achieve BCR::ABL1 ≤ 1% at 12 and 24 months, but again no significant association with CML-related deaths is found.

Conclusions

Our real-world data, prospectively collected in a large number of CML patients treated with first-line imatinib or 2ndG TKIs, show that 1) only a minority (less than one-fifth) of the deaths observed over a 5-year period are CML-related; 2) half of the CML-related deaths occur in high-risk ELTS patients, who represent only 12% of all CML cases in the Italian population, while the risk of dying from CML-related causes is marginal (0.35%) in low-risk ELTS patients, who represent approximately two-thirds of all CML patients; 3) 2ndG TKIs are not able to prevent the occurrence of progression and subsequent CML-related deaths as more CML-related deaths were observed in patients treated with 2ndG TKIs; 4) the ELTS scoring system is highly predictive of the probability of survival in CML patients, regardless of the first-line treatment chosen; 5) Failure to achieve molecular milestones represented by BCR::ABL1 ≤1% at 12 months or ≤0.1% at 24 months, is associated with statistically significant worse survival, although not due to CML-related deaths. The reasons for this association are unclear at this time and are the subject of further investigation.

Disclosures: Giai: Novartis: 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; Alexion: 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; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bonifacio: Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. 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. Stagno: Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Galimberti: 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; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Bocchia: Novartis: Honoraria, Other: travel grant; Incyte: Honoraria, Other: travel grant; Abbvie: Honoraria, Other: travel grants. 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; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Novartis: Speakers Bureau. Fozza: Amgen: Research Funding; Soby: Consultancy; BMS: Research Funding; Sanofi: Research Funding. Musto: Beigene: Consultancy, Honoraria. 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. Breccia: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; BMS: Honoraria; AOP: Honoraria; GSK: Honoraria. Saglio: Novartis: Consultancy, Speakers Bureau; Hikma: Speakers Bureau; Ascentage Pharma: Consultancy.

*signifies non-member of ASH